Kcnq2-5 channel activator

ABSTRACT

The present invention relates to a compound represented by the general formula (I) (wherein the definition of each group has the same meaning as described in the specification). The compound is useful as preventive and/or therapeutic agent for KCNQ2-5 channel-related diseases.

TECHNICAL FIELD

The present invention relates to a compound represented by the generalformula (I):

(wherein all the symbols represent the same meanings as given below), asalt thereof, a solvate thereof, or a cocrystal thereof (hereinafter,also abbreviated as the compound of the present invention).

BACKGROUND ART

It has been found that a KCNQ channel has five subtypes including KCNQ1,KCNQ2, KCNQ3, KCNQ4, and KCNQ5. Among them, KCNQs 2-5 other than KCNQ1are expressed in the nociceptive sensory system such as spinal dorsalroot ganglion and spinal cord. The activation of the KCNQ2-5 channelcauses hyperpolarization of the nerve cell in a nociceptive signalpathway.

It has been reported that KCNQ2-5 channel activator is useful fortreatment for many disorders characterized by neuron excitatorydisorders including epilepsy, pain, migraine, and anxiety disorders (seeNon-Patent Literature 1). Actually, retigabine as a KCNQ2-5 channelactivator has been marketed as an antiepileptic drug.

Furthermore, in recent years, it has been also reported that theretigabine is useful for treatment for urinary bladder disorders (forexample, overactive urinary bladder) (see Non-Patent Literatures 2 and3).

It is considered that since the overactive urinary bladder is caused bypotential overactivity of the detrusor muscle, a muscarinic receptorantagonist having an effect of mainly inhibiting contraction of theurinary bladder has been widely used for treatment for overactiveurinary bladder. However, the muscarinic receptor is present not only inthe urinary bladder but also in the salivary gland, the intestinaltract, the ciliary muscle, and the like, and the muscarinic receptor hasalso a functional role. Therefore, adverse reactions such as dry mouth,constipation, and nephelopsia may occur concurrently. Furthermore, thereis a concern that the effect of inhibiting contraction of the urinarybladder by the muscarinic receptor antagonist may cause adversereactions such as difficulty of urination, increase in the amount ofresidual urine, and urodialysis. Therefore, sufficient therapeuticeffect cannot be necessarily provided. Furthermore, as a drug toovercome the problems of the muscarinic receptor antagonist, a selectiveβ3 adrenergic receptor agonist was put on the market in 2011 in Japan.It is suggested that the selective β3 adrenergic receptor agonistenhances the urine collection function by relaxing action of the urinarybladder, while it gives less effect on the urination function. Since theselective β3 adrenergic receptor agonist exhibits the relaxing action ofthe urinary bladder not by contractile stimulation, it is expected tohave an effect in a wide range of patients. On the other hand, increasein use increases a risk of Q-T extension and shows increase in thecardiac rate by the effect of β cardiac receptor, and which is arestriction factor of the usage.

As mentioned above, in this region, a drug having a relaxing action ofthe urinary bladder not by the contractile stimulation, and less adversereaction have been demanded. The KCNQ2-5 channel activator is expectedas a drug that responds to these unmet medical needs.

To date, as a KCNQ activator having a monocyclic amide skeleton, forexample, a compound represented by the general formula (a) is known:

(wherein Za is O or S; qa is 0 or 1; R^(a1) and R^(a2) are eachindependently selected from the group consisting of halogen, cyano,amino, C₁₋₆-alkyl (alkenyl/alkynyl), and the like; R^(a3) is selectedfrom the group consisting of C₁₋₈-alkyl (alkenyl/alkynyl),C₃₋₈-cycloalkyl (cycloalkenyl), C₃₋₈-cycloalkyl(cycloalkenyl)-C₁₋₆-alkyl (alkenyl/alkynyl), aryl-C₁₋₆-alkyl(alkenyl/alkynyl), aryl-C₃₋₈-cycloalkyl (cycloalkenyl), and the like;R^(a4) is selected from the group consisting of halogen, cyano,C₁₋₆-alkyl (alkenyl/alkynyl), C₃₋₈-cycloalkyl (cycloalkenyl),C₃₋₈-cycloalkyl (cycloalkenyl)-C₁₋₆-alkyl (alkenyl/alkynyl), and thelike (definitions of the groups were partially extracted) (see PatentLiterature 1).

However, the compound of the present invention is not included in thegeneral formula (a) of Patent Literature 1. Furthermore, PatentLiterature 1 includes neither description nor suggestion of technique ofachieving the compound of the present invention from the compounddescribed in the Patent Literature 1.

Furthermore, Patent Literature 2 describes the following compound:

(N-ethyl-N′-[2-bromo-4-(hexafluoro-2-hydroxy-2-propyl)phenyl]urea).However, Patent Literature 2 relates to a compound having a hyopotensiveactivity, and includes neither description nor suggestion of the KCNQactivity.

CITATION LIST Patent Literatures

-   Patent Literature 1: International Publication number WO2006/029623-   Patent Literature 2: Japanese Patent Application Unexamined    Publication No. S51-82239

Non-Patent Literatures

-   [Non-Patent Literature 1] Current Topics in Medicinal Chemistry,    Vol. 6, p. 999-1023, 2006-   [Non-Patent Literature 2] The Journal of Urology, Vol. 172, p.    2054-2058, 2004-   [Non-Patent Literature 3] European Journal of Pharmacology, Vol.    638, p. 121-127, 2010

SUMMARY OF THE INVENTION Technical Problems

An object of the present invention is to provide a compound having astrong opening action with respect to KCNQ2-5 channels.

Solution to Problem

In order to solve the above-mentioned problems, the inventors of thepresent invention have keenly studied, and as a result, found that thecompound of the present invention has a strong opening action withrespect to the KCNQ2-5 channels. Furthermore, the present inventors havefound that the compound of the present invention is excellent insolubility, stability and/or safety. Thus, the present inventors havecompleted the present invention.

That is to say, the present invention relates to

(1) a compound represented by the general formula (1):

(wherein X¹ is (1) a nitrogen atom or (2) C—R⁶; X² is (1) a nitrogenatom or (2) C—R⁷; R¹¹ is (1) OR¹ or (2) NH₂; R¹ is (1) a hydrogen atomor (2) a C1-4 alkyl group; R² and R³ are each independently (1) ahydrogen atom, or (2) a C1-4 alkyl group which may be substituted withhalogen, where both R² and R³ are not simultaneously a hydrogen atom;R⁴, R⁵, R⁶, and R⁷ are each independently (1) a hydrogen atom, (2)halogen, (3) a C1-4 alkyl group which may be substituted with halogen,or (4) a C1-4 alkoxy group which may be substituted with halogen, whereboth R⁴ and R⁵ are not simultaneously a hydrogen atom; Y is (1) —NH—,(2) —O—, or (3) a bond; R⁸ is (1) a hydrogen atom or (2) a C1-4 alkylgroup which may be substituted with halogen or a hydroxy group; R⁹ is(1) a ring A, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) aC2-6 alkynyl group, (5) —C1-4 alkylene group-ring A, (6) —C2-4alkenylene group-ring A, (7) —C2-4 alkynylene group-ring A, (8) -ringB-ring C, (9) -ring B—C1-4 alkylene group-ring C, (10) -ring B—C2-4alkenylene group-ring C, (11) -ring B—C2-4 alkynylene group-ring C, or(12) -ring B—O-ring C, where the alkyl group, alkenyl group, alkynylgroup, alkylene group, alkenylene group or alkynylene group each may besubstituted with halogen or a hydroxy group; the ring A is (1) C3-8cycloalkane, (2) 3- to 8-membered heterocycloalkane, (3) a C3-12monocyclic or bicyclic unsaturated carbocyclic ring, or which may bepartially saturated, or (4) 3- to 12-membered monocyclic or bicyclicunsaturated heterocycle including one to four heteroatoms selected froman oxygen atom, a nitrogen atom, and a sulfur atom, or which may bepartially saturated; ring B and ring C are each independently (1) C3-8cycloalkane, (2) 3- to 8-membered heterocycloalkane, (3) a C3-7monocyclic unsaturated carbocyclic ring, or which may be partiallysaturated, or (4) 3- to 7-membered monocyclic unsaturated heterocycleincluding one to three heteroatoms selected from an oxygen atom, anitrogen atom and a sulfur atom, or which may be partially saturated;where the ring A, ring B and ring C each independently may besubstituted with one to five R¹⁰, and when a plurality of R¹⁰ ispresent, the plurality of R¹⁰ may be the same as or different from eachother; R¹⁰ is (1) halogen, (2) a hydroxy group, (3) a cyano group, (4) aC1-6 alkyl group which may be substituted with halogen or a hydroxygroup, (5) a C1-6 alkoxy group which may be substituted with halogen ora hydroxy group, or (6) an amino group which may be substituted with aC1-4 alkyl group or a C2-5 acyl group) (excludingN-ethyl-N′-[2-bromo-4-(hexafluoro-2-hydroxy-2-propyl)phenyl]urea), asalt thereof, a solvate thereof, or a cocrystal thereof;(2) the compound described in the above (1), wherein Y is —NH— or abond, a salt thereof, a solvate thereof, or a cocrystal thereof;(3) the compound described in the above (1) or (2), wherein X¹ is C—R⁶,and X² is C—R⁷, a salt thereof, a solvate thereof, or a cocrystalthereof;(4) the compound described in any one of the above (1) to (3), which isrepresented by the general formula (II):

(wherein the symbols represent the same meaning as described in theabove (1)), a salt thereof, a solvate thereof, or a cocrystal thereof;(5) the compound described in any one of the above (1) to (4), whereinR¹ is a hydrogen atom, a salt thereof, a solvate thereof, or a cocrystalthereof;(6) the compound described in any one of the above (1) to (5), whereinone of R² and R³ is a methyl group which may be substituted withhalogen, and the other is a hydrogen atom or a methyl group which may besubstituted with halogen, a salt thereof, a solvate thereof, or acocrystal thereof;(7) the compound described in any one of the above (1) to (6), whereinR⁶ is a hydrogen atom or halogen, and R⁷ is a hydrogen atom, a saltthereof, a solvate thereof, or a cocrystal thereof;(8) the compound described in any one of the above (1) to (7), which isrepresented by the General formula (II-1):

(wherein R⁶ is a hydrogen atom or halogen, and the other symbolsrepresent the same meaning as described in the above (1)), a saltthereof, a solvate thereof, or a cocrystal thereof;(9) the compound described in any one of the above (1) to (7), which isrepresented by the general formula (II-2):

(wherein R⁶ is a hydrogen atom or halogen, and the other symbolsrepresent the same meaning as described in the above (1)), a saltthereof, a solvate thereof, or a cocrystal thereof;(10) the compound described in any one of the above (1) to (9), whereinR⁴ and R⁵ are each independently halogen or a methyl group, a saltthereof, a solvate thereof, or a cocrystal thereof;(11) the compound described in any one of the above (1) to (10), whereinR⁸ is a hydrogen atom or a methyl group, a salt thereof, a solvatethereof, or a cocrystal thereof;(12) the compound described in the above (1), wherein the compound is:

-   (1)    1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea,-   (2)    1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea,-   (3)    1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea,-   (4)    1-[(5-chloro-2-pyridinyl)methyl]-3-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea,-   (5)    1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea,-   (6)    1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea,-   (7)    1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea,-   (8)    1-[(5-chloro-2-pyridinyl)methyl]-3-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea,-   (9)    1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea,-   (10)    1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea,-   (11)    1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-5-pyrimidinyl]methyl}urea,-   (12)    1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea,-   (13)    1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea,-   (14)    1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea,-   (15)    1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-5-pyrimidinyl]methyl}urea,-   (16)    1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea,-   (17)    1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea,    or-   (18)    1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea,    a salt thereof, a solvate thereof, or a cocrystal thereof;    (13) a pharmaceutical composition comprising a compound represented    by the general formula (I), a salt thereof, a solvate thereof, or a    cocrystal thereof, and a pharmaceutically acceptable carrier;    (14) the pharmaceutical composition described in the above (13),    which is a preventive and/or therapeutic agent for a KCNQ2-5    channel-related disease;    (15) the pharmaceutical composition described in the above (14),    wherein the KCNQ2-5 channel-related disease is dysuria;    (16) the pharmaceutical composition described in the above (15), the    dysuria is overactive urinary bladder;    (17) a method for preventing and/or treating a KCNQ2-5    channel-related disease, the method comprising: administering an    effective amount of the compound represented by the general formula    (I), a salt thereof, a solvate thereof, or a cocrystal thereof, to a    mammal;    (18) a compound represented by the general formula (I), a salt    thereof, a solvate thereof, or a cocrystal thereof, for preventing    and/or treating a KCNQ2-5 channel-related disease;    (19) use of a compound represented by the general formula (I), a    salt thereof, a solvate thereof, or a cocrystal thereof, for    producing a preventive and/or therapeutic agent for a KCNQ2-5    channel-related disease;    (20) a compound represented by the general formula (I-1):

(wherein R¹ is (1) a hydrogen atom or (2) a C1-4 alkyl group; R² and R³are each independently (1) a hydrogen atom, or (2) a C1-4 alkyl groupwhich may be substituted with halogen, where both R² and R³ are notsimultaneously a hydrogen atom; R⁴ and R⁵ are each independently (1) ahydrogen atom, (2) halogen, (3) a C1-4 alkyl group which may besubstituted with halogen, or (4) a C1-4 alkoxy group which may besubstituted with halogen, where both R⁴ and R⁵ are not simultaneously ahydrogen atom; R⁶, and R⁷ are each independently a hydrogen atom orhalogen; Y is (1) —NH—, (2) —CH₂—, (3) —O—, or (4) a bond; R⁸ is (1) ahydrogen atom or (2) a C1-4 alkyl group which may be substituted withhalogen or a hydroxy group; R⁹ is (1) a ring A, (2) a C1-6 alkyl group,(3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) —C1-4 alkylenegroup-ring A, (6) —C2-4 alkenylene group-ring A, (7) —C2-4 alkynylenegroup-ring A, (8) -ring B-ring C, (9) -ring B—C1-4 alkylene group-ringC, (10) -ring B—C2-4 alkenylene group-ring C, or (11) -ring B—C2-4alkynylene group-ring C, where the alkyl group, alkenyl group, alkynylgroup, alkylene group, alkenylene group or alkynylene group each may besubstituted with halogen or a hydroxy group; the ring A is (1) C3-8cycloalkane, (2) 3- to 8-membered heterocycloalkane, (3) a C5-12monocyclic or bicyclic unsaturated carbocyclic ring, or which may bepartially saturated, or (4) 5- to 12-membered monocyclic or bicyclicunsaturated heterocycle including one to four heteroatoms selected froman oxygen atom, a nitrogen atom, and a sulfur atom, or which may bepartially saturated; ring B and ring C are each independently (1) C3-8cycloalkane, (2) 3- to 8-membered heterocycloalkane, (3) a C5-7monocyclic unsaturated carbocyclic ring, or which may be partiallysaturated, or (4) 5- to 7-membered monocyclic unsaturated heterocycleincluding one to three heteroatoms selected from an oxygen atom, anitrogen atom and a sulfur atom, or which may be partially saturated;where the ring A, ring B and ring C each independently may besubstituted with one to five R¹⁰, and when a plurality of R¹⁰ ispresent, the plurality of R¹⁰ may be the same as or different from eachother; R¹⁰ is (1) halogen, (2) a hydroxy group, (3) a cyano group, (4) aC1-6 alkyl group which may be substituted with halogen or a hydroxygroup, or (5) a C1-6 alkoxy group which may be substituted with halogenor a hydroxy group), a salt thereof, a solvate thereof, or a cocrystalthereof;(21) the compound described in the above (20), wherein Y is —NH—, —CH₂—,or a bond, a salt thereof, a solvate thereof, or a cocrystal thereof;(22) the compound described in the above (20) or (21), which isrepresented by the general formula (II):

(wherein the symbols represent the same meaning as described in theabove (20)), a salt thereof, a solvate thereof, or a cocrystal thereof;(23) the compound described in any one of the above (20) to (22),wherein R¹ is a hydrogen atom, a salt thereof, a solvate thereof, or acocrystal thereof;(24) the compound described in any one of the above (20) to (23),wherein one of R² and R³ is a methyl group which may be substituted withhalogen, and the other is a methyl group which may be substituted with ahydrogen atom or halogen a salt thereof, a solvate thereof, or acocrystal thereof;(25) the compound described in any one of the above (20) to (24),wherein R⁷ is a hydrogen atom, a salt thereof, a solvate thereof, or acocrystal thereof;(26) the compound described in any one of the above (20) to (25), whichis represented by the general formula (II-1):

(wherein the symbols represent the same meaning as described in theabove (20)), a salt thereof, a solvate thereof, or a cocrystal thereof;(27) the compound described in any one of the above (20) to (25), whichis represented by the general formula (II-2):

(wherein the symbols represent the same meaning as described in theabove (20)), a salt thereof, a solvate thereof, or a cocrystal thereof;(28) the compound described in any one of the above (20) to (27),wherein R⁴ and R⁵ are each independently halogen or a methyl group, asalt thereof, a solvate thereof, or a cocrystal thereof;(29) the compound described in any one of the above (20) to (28),wherein R⁸ is a hydrogen atom or a methyl group, a salt thereof, asolvate thereof, or a cocrystal thereof, and the like.

Advantageous Effects of the Invention

The compound of the present invention is useful as preventive and/ortherapeutic agent for KCNQ2-5 channel-related diseases.

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention is described in detail.

In the present invention, the C1-4 alkyl group means a straight or abranched C1-4 alkyl group. Examples of the C1-4 alkyl group includemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

In the present invention, the C2-4 alkyl group means a straight or abranched C2-4 alkyl group. Examples of the C2-4 alkyl group includeethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

In the present invention, the C1-6 alkyl group means a straight or abranched C1-6 alkyl group. Examples of the C1-6 alkyl group includemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, 3-methyl pentyl, andthe like.

In the present invention, the C2-5 acyl group means a straight or abranched C2-5 acyl group. Examples of the C2-5 acyl group includeacetyl, propionyl, butanoyl, pentanoyl, and the like.

In the present invention, the C2-6 alkenyl group means a straight or abranched C2-6 alkenyl group having at least one carbon-carbon doublebond. Examples of the C2-6 alkenyl group include ethenyl,1-propene-1-yl, 1-propene-2-yl, 2-propene-1-yl, 1-butene-1-yl,1-butene-2-yl, 3-butene-1-yl, 3-butene-2-yl, 2-butene-1-yl,2-butene-2-yl, 2-methyl-1-propene-1-yl, 2-methyl-2-propene-1-yl,1,3-butadiene-1-yl, 1,3-butadiene-2-yl, and the like.

In the present invention, the C2-6 alkynyl group means a straight or abranched C2-6 alkynyl group having at least one carbon-carbon triplebond. Examples of the C2-6 alkynyl group include ethynyl,1-propyne-1-yl, 2-propyne-1-yl, 1-butyne-1-yl, 3-butyne-1-yl,3-butyne-2-yl, 2-butyne-1-yl, and the like.

In the present invention, the C1-4 alkylene group means a straight or abranched C1-4 alkylene group. Examples of the C1-4 alkylene groupinclude methylene, ethylene, methyl methylene, ethyl methylene,propylene, butylene, isopropylene, isobutylene, sec-butylene,tert-butylene, and the like.

In the present invention, the C2-4 alkenylene group means a straight ora branched C2-4 alkenylene group. Examples of the C2-4 alkenylene groupinclude ethenylene, 1-propenylene, 2-propenylene, 1-butenylene,2-butenylene, 3-butenylene, and the like.

In the present invention, the C2-4 alkynylene group means a straight ora branched C2-4 alkynylene group. Examples of the C2-4 alkynylene groupinclude ethynylene, 1-propynylene, 2-propynylene, 1-buthynylene,2-buthynylene, 3-buthynylene, and the like.

In the present invention, the C1-4 alkoxy group means a straight or abranched C1-4 alkoxy group. Examples of the C1-4 alkoxy group includemethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy,and the like.

In the present invention, C1-6 alkoxy group means a straight or abranched C1-6 alkoxy group. Examples of the C1-6 alkoxy group includemethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy,pentyloxy, isopentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, and thelike.

In the present invention, halogen means fluorine, chlorine, bromine,iodine, and the like.

In the present invention, the C3-8 cycloalkane is a C3-8 saturatedhydrocarbon ring, and may include a spiro bond or cross-linking.Examples of the C3-8 cycloalkane include cyclopropane, cyclobutane,cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane,bicyclo[2.2.2]octane, cycloheptane, cyclooctane, perhydropentalene,cubane, and the like.

In the present invention, specific examples of the C3-8 monocycliccycloalkane include cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, and cyclooctane.

In the present invention, specific examples of the C3-6 monocycliccycloalkane include cyclopropane, cyclobutane, cyclopentane, andcyclohexane.

In the present invention, the 3- to 8-membered heterocycloalkane is a 3-to 8-membered saturated heterocycle including one to three heteroatomsselected from an oxygen atom, a nitrogen atom and a sulfur atom, and mayinclude a spiro bond or cross-linking. Specific examples of the 3- to8-membered heterocycloalkane include aziridine, oxirane, thiirane,azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran,tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran,azabicyclo[2.2.1]heptane, oxabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[2.2.2]octane, perhydroazepine,perhydrooxepin, perhydrothiepin, azabicyclo[3.2.1]octane,oxabicyclo[3.2.1]octane, imidazolidine, pyrazolidine, tetrahydro-oxazole(oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole(thiazolidine), tetrahydro-isothiazole (isothiazolidine), dioxolane,dithiolane, piperazine, perhydropyrimidine, perhydropyridazine,tetrahydroxazine, tetrahydrothiazine, morpholine, thiomorpholine,oxathiane, dioxane, dithiane, diazabicyclo[2.2.2]octane,perhydrodiazepine, perhydro-oxazepine, perhydrothiazepine, triazolidine,tetrahydrofurazan, tetrahydrooxadiazole (oxadiazolidine),tetrahydrothiadiazole (thiadiazolidine), tetrahydro-oxadiazine,tetrahydrothiadiazine, perhydro-oxadiazepine, perhydrothiadiazepine, andthe like.

In the present invention, specific examples of the 3- to 7-memberedmonocyclic heterocycloalkane including one oxygen atom as the heteroatominclude oxirane, oxetane, tetrahydrofuran, tetrahydropyran,perhydrooxepin, and the like.

In the present invention, specific examples of the 3- to 7-memberedmonocyclic heterocycloalkane including one oxygen atom or nitrogen atomas the heteroatom include aziridine, oxirane, azetidine, oxetane,pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran,perhydroazepine, perhydrooxepin, and the like.

In the present invention, specific examples of the 3- to 7-memberedmonocyclic heterocycloalkane including one nitrogen atom as theheteroatom include aziridine, azetidine, pyrrolidine, piperidine,perhydroazepine, and the like.

In the present invention, specific examples of the “C3-12 monocyclic orbicyclic unsaturated carbocyclic ring, or which may be partiallysaturated” include cyclopropene, cyclobutene, cyclopentene,cyclopentadiene, cyclohexene, cyclohexadiene, benzene, cycloheptene,cycloheptadiene, cyclooctene, cyclooctadiene, pentalene, indene, indan,dihydronaphthalene, tetrahydronaphthalene, azulene, naphthalene,heptalene, and the like.

In the present invention, specific examples of the “C5-12 monocyclic orbicyclic unsaturated carbocyclic ring or which may be partiallysaturated” include cyclopentene, cyclopentadiene, cyclohexene,cyclohexadiene, benzene, cycloheptene, cycloheptadiene, cyclooctene,cyclooctadiene, pentalene, indene, indan, dihydronaphthalene,tetrahydronaphthalene, azulene, naphthalene, heptalene, and the like.

In the present invention, specific examples of the “C3-7 monocyclicunsaturated carbocyclic ring or which may be partially saturated”include cyclopropene, cyclobutene, cyclopentene, cyclopentadiene,cyclohexene, cyclohexadiene, benzene, cycloheptene, cycloheptadiene, andthe like.

In the present invention, specific examples of the “C5-7 monocyclicunsaturated carbocyclic ring or which may be partially saturated”include cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene,benzene, cycloheptene, cycloheptadiene, and the like.

In the present invention, specific examples of the “C5-6 monocyclicunsaturated carbocyclic ring or which may be partially saturated”include cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene,benzene, and the like.

In the present invention, specific examples of the “C8-10 bicyclicunsaturated carbocyclic ring or which may be partially saturated”include pentalene, indene, indan, dihydronaphthalene,tetrahydronaphthalene, azulene, naphthalene, and the like.

In the present invention, specific examples of the “3- to 12-memberedmonocyclic or bicyclic unsaturated heterocycle including one to fourheteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfuratom, or which may be partially saturated” include azirine, oxirene,thiirene, azete, pyrroline, imidazoline, triazoline, tetrazoline,pyrazoline, dihydrofuran, dihydrothiophene, dihydrooxazole,dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrofurazan,dihydrooxadiazole, dihydrothiadiazole, pyrrole, imidazole, triazol,tetrazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, thiadiazole, pyran, thiopyran,oxazine, oxadiazine, thiazine, thiadiazine, dihydropyridine,tetrahydropyridine, dihydropyrazine, tetrahydropyrazine,dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine,tetrahydropyridazine, dihydropyran, dihydrothiopyran, dihydrooxazine,dihydrooxadiazine, dihydrothiazine, dihydrothiadiazine, pyridine,pyrazine, pyrimidine, pyridazine, azepine, diazepine, oxepin, thiepin,oxazepine, oxadiazepine, thiazepine, thiadiazepin, dihydroazepine,tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrooxepin,tetrahydrooxepin, dihydrothiepin, tetrahydrothiepin, dihydrooxazepine,tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,dihydrothiazepine, tetrahydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, indolizine, indoline, isoindoline,dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene,dihydroisobenzothiophene, dihydroindazole, dihydrobenzoxazole,dihydrobenzothiazole, dihydrobenzimidazole, dioxaindan, benzodithiolane,indole, isoindole, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, indazole, purine, benzoxazole, benzothiazole,benzimidazole, benzofurazan, benzothiadiazole, benzotriazol,dithianaphthalene, quinolizine, chromene, dihydroquinoline,tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, benzooxathiane, dihydrobenzooxazine,dihydrobenzothiazine, pyrazinomorpholine, benzodioxan, chroman,benzodithiane, quinoline, isoquinoline, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzooxepin,benzooxazepine, benzooxadiazepine, benzothiepin, benzothiazepine,benzothiadiazepine, benzoazepine, benzodiazepine, dihydrobenzoazepine,tetrahydrobenzoazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzooxazepine, tetrahydrobenzooxazepine, and thelike.

In the present invention, specific examples of the “5- to 12-memberedmonocyclic or bicyclic unsaturated heterocycle including one to fourheteroatoms selected from an oxygen atom, a nitrogen atom and a sulfuratom, or which may be partially saturated” include pyrroline,imidazoline, triazoline, tetrazoline, pyrazoline, dihydrofuran,dihydrothiophene, dihydrooxazole, dihydroisoxazole, dihydrothiazole,dihydroisothiazole, dihydrofurazan, dihydrooxadiazole,dihydrothiadiazole, pyrrole, imidazole, triazol, tetrazole, pyrazole,furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan,oxadiazole, thiadiazole, pyran, thiopyran, oxazine, oxadiazine,thiazine, thiadiazine, dihydropyridine, tetrahydropyridine,dihydropyrazine, tetrahydropyrazine, dihydropyrimidine,tetrahydropyrimidine, dihydropyridazine, tetrahydropyridazine,dihydropyran, dihydrothiopyran, dihydrooxazine, dihydrooxadiazine,dihydrothiazine, dihydrothiadiazine, pyridine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, oxepin, thiepin, oxazepine,oxadiazepine, thiazepine, thiadiazepine, dihydroazepine,tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrooxepin,tetrahydrooxepin, dihydrothiepin, tetrahydrothiepin, dihydrooxazepine,tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,dihydrothiazepine, tetrahydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, indolizine, indoline, isoindoline,dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene,dihydroisobenzothiophene, dihydroindazole, dihydrobenzoxazole,dihydrobenzothiazole, dihydrobenzimidazole, dioxaindan, benzodithiolane,indole, isoindole, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, indazole, purine, benzoxazole, benzothiazole,benzimidazole, benzofurazan, benzothiadiazole, benzotriazol,dithianaphthalene, quinolizine, chromene, dihydroquinoline,tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, benzooxathiane, dihydrobenzooxazine,dihydrobenzothiazine, pyrazinomorpholine, benzodioxan, chroman,benzodithiane, quinoline, isoquinoline, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzooxepin,benzooxazepine, benzooxadiazepine, benzothiepin, benzothiazepine,benzothiadiazepine, benzoazepine, benzodiazepine, dihydrobenzoazepine,tetrahydrobenzoazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzooxazepine, tetrahydrobenzooxazepine, and thelike.

In the present invention, specific examples of the “3- to 7-memberedmonocyclic unsaturated heterocycle including one to three heteroatomsselected from an oxygen atom, a nitrogen atom, and a sulfur atom, orwhich may be partially saturated” include azirine, oxirene, thiirene,azete, pyrroline, dihydrofuran, dihydrothiophene, pyrrole, furan,thiophene, pyran, thiopyran, dihydropyridine, tetrahydropyridine,dihydropyran, dihydrothiopyran, pyridine, azepine, oxepin, thiepin,dihydroazepine, tetrahydroazepine, dihydrooxepin, tetrahydrooxepin,dihydrothiepin, tetrahydrothiepin, imidazoline, pyrazoline,dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole,imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxazine,thiazine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine,tetrahydropyrimidine, dihydropyridazine, tetrahydropyridazine,dihydrooxazine, dihydrothiazine, pyrazine, pyrimidine, pyridazine,diazepine, oxazepine, thiazepine, dihydrodiazepine, tetrahydrodiazepine,dihydrooxazepine, tetrahydrooxazepine, dihydrothiazepine,tetrahydrothiazepine, triazoline, dihydrofurazan, dihydrooxadiazole,dihydrothiadiazole, triazol, furazan, oxadiazole, thiadiazole,oxadiazine, thiadiazine, dihydrooxadiazine, dihydrothiadiazine,oxadiazepine, thiadiazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,and the like.

In the present invention, specific examples of the “5- to 7-memberedmonocyclic unsaturated heterocycle including one to three heteroatomsselected from an oxygen atom, a nitrogen atom and a sulfur atom, orwhich may be partially saturated” include pyrroline, dihydrofuran,dihydrothiophene, pyrrole, furan, thiophene, pyran, thiopyran,dihydropyridine, tetrahydropyridine, dihydropyran, dihydrothiopyran,pyridine, azepine, oxepin, thiepin, dihydroazepine, tetrahydroazepine,dihydrooxepin, tetrahydrooxepin, dihydrothiepin, tetrahydrothiepin,imidazoline, pyrazoline, dihydrooxazole, dihydroisoxazole,dihydrothiazole, dihydroisothiazole, imidazole, pyrazole, oxazole,isoxazole, thiazole, isothiazole, oxazine, thiazine, dihydropyrazine,tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine,dihydropyridazine, tetrahydropyridazine, dihydrooxazine,dihydrothiazine, pyrazine, pyrimidine, pyridazine, diazepine, oxazepine,thiazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrooxazepine,tetrahydrooxazepine, dihydrothiazepine, tetrahydrothiazepine,triazoline, dihydrofurazan, dihydrooxadiazole, dihydrothiadiazole,triazol, furazan, oxadiazole, thiadiazole, oxadiazine, thiadiazine,dihydrooxadiazine, dihydrothiadiazine, oxadiazepine, thiadiazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, and the like.

In the present invention, specific examples of the “5- to 6-memberedmonocyclic unsaturated heterocycle including one to three heteroatomsselected from an oxygen atom, a nitrogen atom and a sulfur atom, orwhich may be partially saturated” include pyrroline, dihydrofuran,dihydrothiophene, imidazoline, pyrazoline, dihydrooxazole,dihydroisoxazole, dihydrothiazole, dihydroisothiazole, triazoline,dihydrofurazan, dihydrooxadiazole, dihydrothiadiazole, pyran, thiopyran,dihydropyridine, tetrahydropyridine, dihydropyran, dihydrothiopyran,oxazine, thiazine, dihydropyrazine, tetrahydropyrazine,dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine,tetrahydropyridazine, dihydrooxazine, dihydrothiazine, oxadiazine,thiadiazine, dihydrooxadiazine, dihydrothiadiazine, pyrrole, furan,thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,isothiazole, triazol, furazan, oxadiazole, thiadiazole, pyridine,pyrazine, pyrimidine, pyridazine, and the like.

In the present invention, specific examples of the “5- to 6-memberedunsaturated heterocycle including one to three heteroatoms selected froman oxygen atom, a nitrogen atom and a sulfur atom” include pyrrole,furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,isothiazole, triazol, furazan, oxadiazole, thiadiazole, pyridine,pyrazine, pyrimidine, pyridazine, and the like.

In the present invention, specific examples of the “5- to 6-memberedmonocyclic unsaturated nitrogen-containing heterocycle including one tothree heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom, wherein the said 5- to 6-membered monocyclic unsaturatednitrogen-containing heterocycle contains at least one nitrogen atom”include pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyridine,imidazole, pyrazole, furazan, oxadiazole, thiadiazole, pyrazine,pyrimidine, pyridazine, triazol, and the like.

In the present invention, specific examples of the “9- to 10-memberedbicyclic unsaturated heterocycle including one to four heteroatomsselected from an oxygen atom, a nitrogen atom, and a sulfur atom, orwhich may be partially saturated” include indolizine, indoline,isoindoline, dihydrobenzofuran, dihydroisobenzofuran,dihydrobenzothiophene, dihydroisobenzothiophene, dihydroindazole,dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzimidazole,dioxaindan, benzodithiolane, quinolizine, chromene, dihydroquinoline,tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,chroman, dithianaphthalene, dihydrophthalazine, tetrahydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, benzooxathiane,dihydrobenzooxazine, dihydrobenzothiazine, benzodioxan, benzodithiane,pyrazinomorpholine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, benzoxazole, benzothiazole,benzimidazole, benzofurazan, benzothiadiazole, benzotriazol, purine,quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline, pteridine, and the like.

In the present invention, “9- to 10-membered bicyclic unsaturatedheterocycle including one to three heteroatoms selected from an oxygenatom, a nitrogen atom, and a sulfur atom, in which 5- or 6-memberedheterocycle is condensed to benzene, or which may be partiallysaturated” include indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, quinoline, isoquinoline, indazole,benzoxazole, benzothiazole, benzimidazole, phthalazine, quinoxaline,quinazoline, cinnoline, benzofurazan, benzothiadiazole, benzotriazol,indoline, isoindoline, dihydrobenzofuran, dihydroisobenzofuran,dihydrobenzothiophene, dihydroisobenzothiophene, chromene,dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, chroman, dihydroindazole, dihydrobenzoxazole,dihydrobenzothiazole, dihydrobenzimidazole, dioxaindan, benzodithiolane,dithianaphthalene, dihydrophthalazine, tetrahydrophthalazine,dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,benzooxathiane, dihydrobenzooxazine, dihydrobenzothiazine, benzodioxan,benzodithiane, and the like.

In the present invention, when the number of substituents is notspecified, the number of substituents, if present, is intended to be oneor more.

In the present invention, each substituent is independently defined foreach occurrence in the definition in the general formula. For example,when more than one substituents R¹⁰ are present on the “ring A” or the“ring B” and/or the “ring C”, respectively, each substituent is selectedindependently for each occurrence, substituents may be the same as ordifferent from each other.

In the present invention, the KCNQ2-5 channels mean a KCNQ channel inwhich four of each of the subtypes KCNQ2 to KCNQ5 are gathered to form ahomotetramer or a heterotetramer. Examples thereof include homotetramerssuch as KCNQ2, KCNQ3, KCNQ4, and KCNQ5 channel, or heterotetramers suchas KCNQ2/3, KCNQ3/4, KCNQ3/5 channel, and the like. Preferable examplesinclude KCNQ2/3, KCNQ4 and/or KCNQ5 channel.

In the present invention, the KCNQ2-5 channel activator refers to acompound having an opening action with respect to the KCNQ2-5 channels(preferably, KCNQ2/3, KCNQ4 and/or KCNQ5 channel). In the presentinvention, a KCNQ channel activation action has the same meaning as thatof a KCNQ channel opening action.

In the present invention, X¹ is preferably C—R⁶.

In the present invention, X² is preferably C—R⁷.

In the present invention, R¹¹ is preferably OR¹. Furthermore, OH and NH₂are also preferable.

In the present invention, Y is preferably —NH— or a bond, and morepreferably —NH—.

In the present invention, R¹ is preferably a hydrogen atom or a methylgroup, and more preferably a hydrogen atom.

In the present invention, R² is preferably a hydrogen atom or a C1-2alkyl group which may be substituted with halogen, more preferably ahydrogen atom or a methyl group which may be substituted with halogen,and further more preferably a methyl group or a trifluoromethyl group.

In the present invention, R³ is preferably a hydrogen atom or a C1-2alkyl group which may be substituted with halogen, more preferably ahydrogen atom or a methyl group which may be substituted with halogen,and further more preferably a hydrogen atom, a methyl group or atrifluoromethyl group.

In the present invention, the combination of R² and R³ is preferably acombination in which at least one of R² and R³ is a methyl group whichmay be substituted with halogen, and the other is a hydrogen atom or amethyl group which may be substituted with halogen, and more preferablya combination in which at least one of R² and R³ is a trifluoromethylgroup, and the other is a hydrogen atom or a methyl group.

In the present invention, R⁴ is preferably a hydrogen atom, a halogen, aC1-4 alkyl group or a C1-4 alkoxy group, more preferably a hydrogenatom, halogen, or a C1-4 alkyl group, further preferably halogen or amethyl group, and particularly preferably halogen.

In the present invention, R⁵ is preferably a hydrogen atom, a halogen, aC1-4 alkyl group or a C1-4 alkoxy group, more preferably a hydrogenatom, halogen, or a C1-4 alkyl group, further preferably halogen or amethyl group, and particularly preferably halogen.

In the present invention, R⁶ is preferably a hydrogen atom or a halogen,and further preferably a hydrogen atom.

In the present invention, R⁷ is preferably a hydrogen atom or a halogen,and further preferably a hydrogen atom.

In the present invention, it is preferable that at least one of R⁶ andR⁷ is a hydrogen atom, and more preferable that both of R⁶ and R⁷ are ahydrogen atom.

In the present invention, R⁸ is preferably a hydrogen atom or a methylgroup, and more preferably a hydrogen atom.

In the present invention, R⁹ is preferably (1) a ring A, (2) a C2-4alkyl group which may be substituted with halogen or a hydroxy group,(3) -ring B-ring C, (4) -ring B-methylene-ring C, or (5) -ring B—O-ringC. Herein, the rings each independently may be substituted with one tofive R¹⁰. R⁹ is more preferably a ring A substituted with one to fiveR¹⁰; further preferably a 5- to 6-membered monocyclic unsaturatedheterocycle including one to three heteroatoms selected from an oxygenatom, a nitrogen atom, and a sulfur atom, which may be substituted withone to three substituents (preferably one substituent) each selectedfrom the group consisting of (1) halogen, (2) a C1-4 alkyl group whichmay be substituted with halogen, and (3) a C1-4 alkoxy group which maybe substituted with halogen (preferably selected from the groupconsisting of halogen and a C1-4 alkyl group which may be substitutedwith halogen); and particularly preferably a 5- to 6-membered monocyclicunsaturated nitrogen-containing heterocycle including one to threeheteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfuratom, wherein the said 5- to 6-membered monocyclic unsaturatednitrogen-containing heterocycle contains at least one nitrogen atom,which is substituted with a single substituent of halogen or a C1-4alkyl group which may be substituted with halogen (preferably withhalogen or a trifluoromethyl group).

In the present invention, the ring A is preferably (1) C3-8 monocycliccycloalkane, (2) 3- to 7-membered monocyclic heterocycloalkane includingone oxygen atom as a heteroatom, (3) a C5-7 monocyclic unsaturatedcarbocyclic ring, or which may be partially saturated, (4) a C8-10bicyclic unsaturated carbocyclic ring, or which may be partiallysaturated, (5) a 5- to 7-membered monocyclic unsaturated heterocycleincluding one to three heteroatoms selected from an oxygen atom, anitrogen atom, and a sulfur atom, or which may be partially saturated,(6) a 9- to 10-membered bicyclic unsaturated heterocycle including oneto four heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom, or which may be partially saturated (herein, the rings eachindependently may be substituted with one to five R¹⁰); more preferably(1) a C3-6 monocyclic cycloalkane, (2) a 5- to 6-membered monocyclicheterocycloalkane including one oxygen atom as a heteroatom(tetrahydrofuran and tetrahydropyran), (3) a C5-6 monocyclic unsaturatedcarbocyclic ring or which may be partially saturated, (4) a 5- to6-membered monocyclic unsaturated heterocycle including one to threeheteroatoms selected from an oxygen atom, a nitrogen atom and a sulfuratom, or which may be partially saturated, (5) 9- to 10-memberedbicyclic unsaturated heterocycle including one to three heteroatomsselected from an oxygen atom, a nitrogen atom, and a sulfur atom inwhich 5- or 6-membered heterocycle is condensed to benzene (herein, therings each independently may be substituted with one to five R¹⁰);further preferably, a 5- to 6-membered monocyclic unsaturatedheterocycle including one to three heteroatoms selected from an oxygenatom, a nitrogen atom, and a sulfur atom, which may be substituted withone to three substituents (preferably one substituent) each selectedfrom the group consisting of (1) halogen, (2) a C1-4 alkyl group whichmay be substituted with halogen, and (3) a C1-4 alkoxy group which maybe substituted with halogen (preferably selected from the groupconsisting of halogen and a C1-4 alkyl group which may be substitutedwith halogen); and particularly preferably 5- to 6-membered monocyclicunsaturated nitrogen-containing heterocycle including one to threeheteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfuratom, wherein the said 5- to 6-membered monocyclic unsaturatednitrogen-containing heterocycle contains at least one nitrogen atom,which is substituted with a single substituent of halogen or a C1-4alkyl group which may be substituted with halogen (preferably withhalogen or a trifluoromethyl group).

In the present invention, the ring B is preferably (1) C3-8 monocycliccycloalkane, (2) 3- to 7-membered monocyclic heterocycloalkane includingone oxygen atom as a heteroatom, (3) a C5-7 monocyclic unsaturatedcarbocyclic ring, or which may be partially saturated, or (4) 5- to7-membered monocyclic unsaturated heterocycle including one to threeheteroatoms selected from an oxygen atom, a nitrogen atom and a sulfuratom, or which may be partially saturated (herein the rings eachindependently may be substituted with one to five R¹⁰); more preferably5- to 6-membered monocyclic unsaturated heterocycle including one tothree heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom, which may be substituted with one to three substituents(preferably one substituent) selected from the group consisting of (1)halogen, (2) a C1-4 alkyl group which may be substituted with halogen,(3) a C1-4 alkoxy group which may be substituted with halogen(preferably each selected from the group consisting of halogen and aC1-4 alkyl group which may be substituted with halogen); furtherpreferably 5- to 6-membered monocyclic unsaturated nitrogen-containingheterocycle including one to three heteroatoms selected from an oxygenatom, a nitrogen atom, and a sulfur atom, wherein the said 5- to6-membered monocyclic unsaturated nitrogen-containing heterocyclecontains at least one nitrogen atom, which may be substituted with asingle substituent of halogen or a C1-4 alkyl group which may besubstituted with halogen (preferably with halogen or a trifluoromethylgroup); and particularly preferably 5- to 6-membered monocyclicunsaturated nitrogen-containing heterocycle including one to threeheteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfuratom, wherein the said 5- to 6-membered monocyclic unsaturatednitrogen-containing heterocycle contains at least one nitrogen atom, andwhich does not include more than the substituents described in theformula.

In the present invention, the ring C is preferably (1) C3-8 monocycliccycloalkane, (2) 3- to 7-membered monocyclic heterocycloalkane includingone oxygen atom or a nitrogen atom as a heteroatom, (3) a C5-7monocyclic unsaturated carbocyclic ring, or which may be partiallysaturated, or (4) 5- to 7-membered monocyclic unsaturated heterocycleincluding one to three heteroatoms selected from an oxygen atom, anitrogen atom and a sulfur atom, or which may be partially saturated(herein the rings each independently may be substituted with one to fiveR¹⁰); more preferably (1) C3-8 monocyclic cycloalkane, (2) 3- to7-membered monocyclic heterocycloalkane including one nitrogen atom asheteroatom, or (3) a C5-7 monocyclic unsaturated carbocyclic ring orwhich may be partially saturated (herein, the rings each independentlymay be substituted with one to five R¹⁰); further preferably C3-8monocyclic cycloalkane which may be substituted with one to five R¹⁰, orbenzene which may be substituted with one to three R¹⁰; and particularlypreferably C3-8 monocyclic cycloalkane or benzene.

In the present invention, R¹⁰ is preferably (1) halogen, (2) a hydroxygroup, (3) a cyano group, (4) a C1-4 alkyl group which may besubstituted with halogen or a hydroxy group, or (5) a C1-4 alkoxy groupwhich may be substituted with halogen or a hydroxy group; morepreferably (1) halogen, (2) a C1-4 alkyl group which may be substitutedwith halogen, or (3) a C1-4 alkoxy group which may be substituted withhalogen; further preferably (1) halogen or (2) a C1-4 alkyl group whichmay be substituted with halogen; and particularly preferably halogen ora trifluoromethyl group.

In the present invention, a compound of the general formula (I)including the aforementioned preferable combination is preferable.

In the present invention, a preferable compound includes a compoundrepresented by the general formula (I-1):

(wherein the symbols represent the same meanings as defined above), asalt thereof, a solvate thereof, or a cocrystal thereof.

In the present invention, a preferable compound includes a compoundrepresented by the general formula (II):

(wherein the symbols represent the same meanings as defined above), asalt thereof, a solvate thereof, or a cocrystal thereof.

Furthermore, in the present invention, a preferable compound includes acompound represented by the general formula (III):

(wherein the symbols represent the same meanings as defined above), asalt thereof, a solvate thereof, or a cocrystal thereof.

The definitions of preferable groups (single or any combination thereof)mentioned above are also applied to the general formula (I-1), (II) or(III).

In the present invention, the compounds of the general formula (I-1),(II) or (III) including the combinations of the above-listed preferablegroups are preferable.

In the present invention, a more preferable compound includes a compoundrepresented by the general formula (II-1):

(wherein R⁶ is a hydrogen atom or halogen, and the other symbolsrepresent the same meanings as defined above), a salt thereof, a solvatethereof, or a cocrystal thereof.

Furthermore, in the present invention, a more preferable compoundincludes a compound represented by the general formula (II-2):

(wherein R⁶ is a hydrogen atom or halogen, and the other symbolsrepresent the same meanings as defined above), a salt thereof, a solvatethereof, or a cocrystal thereof.

The definitions of preferable groups (single or any combination thereof)mentioned above are also applied to the general formula (II-1) or(II-2).

In the present invention, the compounds of the general formula (II-1) or(II-2) including the combinations of the above-listed preferable groupsare preferable.

In the present invention, a further preferable compound includes acompound represented by the general formula (II-1-1):

(wherein R⁴ and R⁵ are each independently (1) a hydrogen atom, (2)halogen, (3) a C1-4 alkyl group, or (4) a C1-4 alkoxy group (preferably,R⁴ and R⁵ are each independently a hydrogen atom, halogen or a C1-4alkyl group), wherein both R⁴ and R⁵ are not simultaneously a hydrogenatom; R⁶ is a hydrogen atom or halogen; R⁸ is (1) a hydrogen atom or (2)a C1-4 alkyl group which may be substituted with halogen or a hydroxygroup (preferably, a hydrogen atom or a methyl group); R⁹ is preferably(1) a ring A, (2) a C2-4 alkyl group which may be substituted withhalogen or a hydroxy group, (3) -ring B-ring C, (4) -ringB-methylene-ring C, or (5) -ring B—O-ring C (R⁹ is preferably a ring A);the ring A is (1) C3-8 monocyclic cycloalkane, (2) 3- to 7-memberedmonocyclic heterocycloalkane including one oxygen atom as a heteroatom,(3) a C5-7 monocyclic unsaturated carbocyclic ring, or which may bepartially saturated, (4) a C8-10 bicyclic unsaturated carbocyclic ring,or which may be partially saturated, (5) 5- to 7-membered monocyclicunsaturated heterocycle including one to three heteroatoms selected froman oxygen atom, a nitrogen atom and a sulfur atom, or which may bepartially saturated, or (6) 9- to 10-membered bicyclic unsaturatedheterocycle including one to four heteroatoms selected from an oxygenatom, a nitrogen atom and a sulfur atom, or which may be partiallysaturated; the ring B is (1) C3-8 monocyclic cycloalkane, (2) 3- to7-membered monocyclic heterocycloalkane including one oxygen atom as aheteroatom, (3) a C5-7 monocyclic unsaturated carbocyclic ring or whichmay be partially saturated, or (4) 5- to 7-membered monocyclicunsaturated heterocycle including one to three heteroatoms selected froman oxygen atom, a nitrogen atom and a sulfur atom, or which may bepartially saturated; the ring C is (1) C3-8 monocyclic cycloalkane, (2)a 3- to 7-membered monocyclic heterocycloalkane including one oxygenatom or one nitrogen atom as a heteroatom, (3) a C5-7 monocyclicunsaturated carbocyclic ring, or which may be partially saturated, or(4) 5- to 7-membered monocyclic unsaturated heterocycle including one tothree heteroatoms selected from an oxygen atom, a nitrogen atom and asulfur atom, or which may be partially saturated; herein the ring A,ring B or ring C each independently may be substituted with one to fiveR¹⁰, and when a plurality of R¹⁰ is present, the plurality of R¹⁰ may bethe same as or different from each other; R¹⁰ is (1) halogen, (2) ahydroxy group, (3) a cyano group, (4) a C1-4 alkyl group which may besubstituted with halogen or a hydroxy group, or (5) a C1-4 alkoxy groupwhich may be substituted with halogen or a hydroxy group), a saltthereof, a solvate thereof, or a cocrystal thereof.

In the present invention, a further preferable compound includes acompound represented by the general formula (II-2-1):

(wherein R⁴ and R⁵ are each independently (1) a hydrogen atom, (2)halogen, (3) a C1-4 alkyl group, or (4) a C1-4 alkoxy group (preferably,R⁴ and R⁵ are each independently a hydrogen atom, halogen or a C1-4alkyl group), wherein both R⁴ and R⁵ are not simultaneously a hydrogenatom; R⁶ is a hydrogen atom or halogen; R⁸ is (1) a hydrogen atom or (2)a C1-4 alkyl group which may be substituted with halogen or a hydroxygroup (preferably, a hydrogen atom or a methyl group); R⁹ is preferably(1) a ring A, (2) a C2-4 alkyl group which may be substituted withhalogen or a hydroxy group, (3) -ring B-ring C, (4) -ringB-methylene-ring C, or (5) -ring B—O-ring C (R⁹ is preferably a ring A);the ring A is (1) C3-8 monocyclic cycloalkane, (2) 3- to 7-memberedmonocyclic heterocycloalkane including one oxygen atom as a heteroatom,(3) a C5-7 monocyclic unsaturated carbocyclic ring, or which may bepartially saturated, (4) a C8-10 bicyclic unsaturated carbocyclic ring,or which may be partially saturated, (5) 5- to 7-membered monocyclicunsaturated heterocycle including one to three heteroatoms selected froman oxygen atom, a nitrogen atom and a sulfur atom, or which may bepartially saturated, or (6) 9- to 10-membered bicyclic unsaturatedheterocycle including one to four heteroatoms selected from an oxygenatom, a nitrogen atom and a sulfur atom, or which may be partiallysaturated; the ring B is (1) C3-8 monocyclic cycloalkane, (2) 3- to7-membered monocyclic heterocycloalkane including one oxygen atom as aheteroatom, (3) a C5-7 monocyclic unsaturated carbocyclic ring or whichmay be partially saturated, or (4) 5- to 7-membered monocyclicunsaturated heterocycle including one to three heteroatoms selected froman oxygen atom, a nitrogen atom and a sulfur atom, or which may bepartially saturated; the ring C is (1) C3-8 monocyclic cycloalkane, (2)a 3- to 7-membered monocyclic heterocycloalkane including one oxygenatom or one nitrogen atom as a heteroatom, (3) a C5-7 monocyclicunsaturated carbocyclic ring, or which may be partially saturated, or(4) 5- to 7-membered monocyclic unsaturated heterocycle including one tothree heteroatoms selected from an oxygen atom, a nitrogen atom and asulfur atom, or which may be partially saturated; herein the ring A,ring B or ring C each independently may be substituted with one to fiveR¹⁰, and when a plurality of R¹⁰ is present, the plurality of R¹⁰ may bethe same as or different from each other; R¹⁰ is (1) halogen, (2) ahydroxy group, (3) a cyano group, (4) a C1-4 alkyl group which may besubstituted with halogen or a hydroxy group, or (5) a C1-4 alkoxy groupwhich may be substituted with halogen or a hydroxy group), a saltthereof, a solvate thereof, or a cocrystal thereof.

In the present invention, a particularly preferable compound is acompound represented by the general formula (II-1-2):

(wherein R⁴ and R⁵ are each independently halogen or a methyl group(preferably, R⁴ and R⁵ are each independently halogen); R⁶ is a hydrogenatom or halogen (preferably, a hydrogen atom); R⁸ is a hydrogen atom ora methyl group (preferably, a hydrogen atom); R⁹ is a 5- to 6-memberedmonocyclic unsaturated heterocycle including one to three heteroatomsselected from an oxygen atom, a nitrogen atom, and a sulfur atom, whichmay be substituted with one to three substituents (preferably onesubstituent) each selected from the group consisting of (1) halogen, (2)a C1-4 alkyl group which may be substituted with halogen, and (3) a C1-4alkoxy group which may be substituted with halogen (preferably selectedfrom the group consisting of halogen and a C1-4 alkyl group which may besubstituted with halogen) (R⁹ is preferably a 5- to 6-memberedmonocyclic unsaturated nitrogen-containing heterocycle including one tothree heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom, wherein the said 5- to 6-membered monocyclic unsaturatednitrogen-containing heterocycle contains at least one nitrogen atom,which is substituted with a single substituent of halogen or a C1-4alkyl group which may be substituted with halogen (preferably withhalogen or a trifluoromethyl group)), a salt thereof, a solvate thereof,or a cocrystal thereof.

In the present invention, a particularly preferable compound is acompound represented by the general formula (II-2-2):

(wherein R⁴ and R⁵ are each independently halogen or a methyl group(preferably, R⁴ and R⁵ are each independently halogen); R⁶ is a hydrogenatom or halogen (preferably, a hydrogen atom); R⁸ is a hydrogen atom ora methyl group (preferably, a hydrogen atom); R⁹ is a 5- to 6-memberedmonocyclic unsaturated heterocycle including one to three heteroatomsselected from an oxygen atom, a nitrogen atom, and a sulfur atom, whichmay be substituted with one to three substituents (preferably onesubstituent) each selected from the group consisting of (1) halogen, (2)a C1-4 alkyl group which may be substituted with halogen, and (3) a C1-4alkoxy group which may be substituted with halogen (preferably selectedfrom the group consisting of halogen and a C1-4 alkyl group which may besubstituted with halogen) (R⁹ is preferably a 5- to 6-memberedmonocyclic unsaturated nitrogen-containing heterocycle including one tothree heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom, wherein the said 5- to 6-membered monocyclic unsaturatednitrogen-containing heterocycle contains at least one nitrogen atom,which is substituted with a single substituent of halogen or a C1-4alkyl group which may be substituted with halogen (preferably withhalogen or a trifluoromethyl group)), a salt thereof, a solvate thereof,or a cocrystal thereof.

In the present invention, a preferable compound is:

-   (1)    1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea,-   (2)    1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea,-   (3)    1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea,-   (4)    1-[(5-chloro-2-pyridinyl)methyl]-3-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea,-   (5)    1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea,-   (6)    1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea,-   (7)    1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea,-   (8)    1-[(5-chloro-2-pyridinyl)methyl]-3-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea,-   (9)    1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea,-   (10)    1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea,-   (11)    1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-5-pyrimidinyl]methyl}urea,-   (12)    1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea,-   (13)    1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea,-   (14)    1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea,-   (15)    1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-5-pyrimidinyl]methyl}urea,-   (16)    1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea,-   (17)    1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea,-   (18)    1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea,    or a stereoisomer thereof, or a salt thereof, a solvate thereof, or    a cocrystal thereof.

The compound of the present invention is preferably a compound in whichthe opening action with respect to the KCNQ2/3 is 100 μM or less, morepreferably 10 μM or less, further preferably 1 μM or less, andparticularly preferably 0.1 μM or less in terms of EC₅₀ value (orECrtg50 (see (1) Biological Example 1 described later)). The compound ofthe present invention is further preferably a compound having theopening action with respect to all the KCNQ2/3, KCNQ4, and KCNQ5channels (in any channels, the EC₅₀ value (or ECrtg 50) is preferably100 μM or less, more preferably 10 μM or less, and further preferably 1μM or less). A method for determining the EC₅₀ value (or ECrtg 50) iswell known to a person skilled in the art (see, for example,Neuropharmacology, Vol. 40, 2001, pp. 888-898, European Journal ofPharmacology, Vol. 437, 2002, pp. 129-137). The EC₅₀ value is determinedpreferably by a fluorescence measurement method, and more preferably bythe method described in the section of (1) Biological Example 1described later.

The compound of the present invention is preferably a compound havingexcellent solubility. In the present invention, the solubility can beevaluated as solubility to a second solution (pH=6.8) of thePharmacopoeia of Japan elution test by, for example, a dimethylsulfoxide (DMSO) precipitation method (see, the section of (3)Solubility test described later). A compound having the solubility of 20μM or more is preferable, more preferably 40 μM or more, furtherpreferably 60 μM or more, and particularly preferably 80 μM or more ispreferable.

The compound of the present invention is preferably a compound havingexcellent metabolic stability. The metabolic stability can be verifiedby a general measurement method using, for example, a liver microsome ofhuman or other animal species (preferably, human). The stability of thecompound in a human liver microsome can be evaluated by, for example,reacting a commercially available human liver microsome and the compoundof the present invention with each other for a predetermined time (forexample, 5 to 30 minutes), and calculating the residual rate incomparison between the reacted sample and unreacted sample (see, (4)Evaluation of Stability in Human Liver Microsome, described later).

The compound of the present invention is preferably a compound that isexcellent in safety. For example, the compound of the present inventionincludes a compound which does not acts on hERG (human ether-a-go-gorelated gene) channel, or a compound which has a weak hERG channelinhibition action. The hERG channel inhibition action (hERG test) can beevaluated by well-known methods, for example, a rubidium method formeasuring flow of rubidium ion (Rb+) in hERG expression cell, and apatch clamp test for measuring HERG current by a patch clamp technique(see, (5) Evaluation of Activity with respect to hERG IKr Current,described later).

In the present invention, unless specifically noted, all of thestereoisomers are included. For example, all of geometrical isomers ofdouble bonds, rings, and fused rings (E-, Z-, cis-, trans-isomers),optical isomers by the presence of an asymmetric carbon atom (R-,S-isomer, α-, β-configurations, enantiomers, diastereomers), opticalactive isomers having optical rotation property (D, L, d, 1-isomers),polar isomers according to chromatographic separation (high-polarityisomer and low-polarity isomer), equilibrium compound, rotamers,mixtures thereof at any rate, and racemic mixtures are included in thepresent invention. Furthermore, the present invention also encompassesall isomers by tautomers.

In the present invention, unless specifically noted, as is apparent to aperson skilled in the art, a symbol:

represents a binding to the far side of the paper (that is to say, theα-configuration),

represents a binding to the front of the paper (that is to say, theβ-configuration), and

represents α-configuration, β-configuration or an arbitrary mixturethereof.

Furthermore, the optically active compound of the present invention isnot limited to a compound having purity of 100%, but may include otherenantiomer or diastereomer having purity of less than 50%. Specificexamples of the racemic mixture include Example5:1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}ureathat is a mixture of Example22(1):1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}ureaand Example25(4):1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea,and the like.

In the present invention, all the mentions about the compound of thepresent invention include a compound represented by the general formula(I), a salt thereof, a solvate thereof, or a cocrystal thereof, and asolvate of the salt of the compound represented by the general formula(I), or a cocrystal thereof.

The compound represented by the general formula (I) is converted into acorresponding salt by a well-known method. As the salt, pharmaceuticallyacceptable salts are preferable. Furthermore, water-soluble salt ispreferable. Appropriate salts include acid addition salts (inorganicacid salts (hydrochloride, hydrobromide, hydroiodide, sulfate,phosphate, nitrate, and the like), organic acid salts (formate, acetate,propionate, trifluoro acetate, lactate, tartrate, oxalate, malonate,succinate, fumarate, malate, maleate, benzoate, citrate,methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate,isethionate, glucuronate, gluconate, aspartate, glutamate, and thelike).

The compound represented by the general formula (I) and a salt thereofmay be present in a not-solvation form, or in a solvation form withpharmaceutically acceptable solvent such as water and ethanol.Preferable solvates is hydrate. The compound represented by the generalformula (I) and a salt thereof can be converted into a solvate by awell-known method.

The compound represented by the general formula (I) can form a cocrystalwith an appropriate cocrystal former. As the cocrystal, pharmaceuticallyacceptable cocrystal that is formed with a pharmaceutically acceptablecocrystal former is preferable. The cocrystal is typically defined as acrystal that is formed of two or more different molecules byintermolecular interaction that is different from ionic bond.Furthermore, the cocrystal may be a composite of a neutral molecule anda salt. The cocrystal can be prepared by a well-known method, forexample, melting crystallization, recrystallization from a solvent, orphysically pulverizing the components together. Appropriate cocrystalformers include ones described in WO2006/007448.

The compound of the present invention can be administered as a prodrug.For example, a prodrug of the compound represented by the generalformula (I) denotes a compound which is converted to the compoundrepresented by the general formula (I) by a reaction with an enzyme,gastric acid, and the like, in a living body. Prodrugs of the compoundrepresented by the general formula (I) include: compounds in which thehydroxyl group is acylated, alkylated, phosphorylated, or borated, whenthe compounds represented by the general formula (I) have a hydroxylgroup (for example, the compounds represented by the general formula (I)in which the hydroxyl group is acetylated, palmitoylated, propanoylated,pivaloylated, succinylated, fumarylated, alanylated, ordimethylaminomethylcarbonylated). These compounds can be produced bywell-known methods. Furthermore, the prodrug of the compound representedby the general formula (I) may be hydrate or non-hydrate. Furthermore,the prodrug of the compound represented by the general formula (I) maybe a compound which is changed into the compound represented by thegeneral formula (I) under the physiological condition, as described in“Development of Medicaments”, vol. 7 “Molecular Design”, pp. 163-198,published by Hirokawa Shoten in 1990.

The compound represented by the general formula (I) includes allisotopes. That is, includes the compounds, wherein at least one atom isreplaced by an atom which having atomic number same as the original atombut atomic mass or mass number different from the atomic mass or massnumber dominant in the natural world. Examples of the isotopes includedin the compound represented by the general formula (I) include ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, ¹²⁵I, andthe like.

[Method for Producing Compound of the Present Invention]

The compound represented by the general formula (I) can be produced bythe well-known methods, for example, the methods described below, themethods conforming to these methods, methods described in Examples, orthe method described in “Comprehensive Organic Transformations: A Guideto Functional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc, 1999)”, or the like, with appropriate modification andin combination thereof. Note here that in the following each productionmethods, each raw material compound may be used as a salt. Such a saltinclude salts described as above-mentioned pharmaceutically acceptablesalts of the general formula (I).

A compound represented by the general formula (I-1) in which R¹¹ is OR¹among the compound represented by the general formula (I) can beproduced by the method shown in the following reaction scheme 1 or 2using a compound represented by the general formula (SM1):

(wherein T represents R¹ or a protective group for a hydroxyl group, andthe other symbols represent the same meanings as mentioned above) as astarting material.

Examples of the protective group for a hydroxyl group in T include amethyl group, an ethyl group, a propyl group, a butyl group, a tritylgroup, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE) group, amethoxyethoxymethyl (MEM) group, a 2-tetrahydropyranyl (THP) group, atrimethylsilyl (TMS) group, a triethylsilyl (TES) group, atert-butyldimethylsilyl (TBDMS) group, a tert-butyldiphenylsilyl (TBDPS)group, an acetyl (Ac) group, a pivaloyl group, a benzoyl group, a benzyl(Bn) group, a p-methoxybenzyl group, an allyloxycarbonyl (Alloc) group,a 2,2,2-trichloroethoxycarbonyl (Troc) group, and the like.

The protective groups are not particularly limited to theabove-described groups, and may include, in addition to theabove-mentioned groups, groups that can be detached easily andselectively. For example, those described in “Protective Groups inOrganic Synthesis (T. W. Greene, John Wiley & Sons Inc, 1999)” may beused.

A compound in which Y is —NH— or —O— among the compound represented bythe general formula (I), that is, a compound represented by the generalformula (1-a):

(wherein Y₁ represents —NH— or —O—, and the other symbols represent thesame meanings as mentioned above) can be produced by a method shown inthe reaction scheme 1:

(wherein all of the symbols represent the same meanings as mentionedabove).

The reaction to form urea or urethane shown in the reaction 1 in thereaction scheme 1 is carried out by, for example, reacting a compoundrepresented by the general formula (SM1) with triphosgene attemperatures from room temperature to 40° C. in an organic solvent(tetrahydrofuran, N-methyl-2-pyrrolidinone, N,N-dimethylformamide,dichloromethane, and the like) in the presence of a base (triethylamine,diisopropyl ethyl amine, and the like) so as to form a correspondingisocyanate, and then reacting with the compound represented by thegeneral formula (1-b) in an organic solvent (tetrahydrofuran,N-methyl-2-pyrrolidinone, dichloromethane, and the like) at temperaturesfrom room temperature to 60° C. in the presence or absence of a base(triethylamine, diisopropyl ethyl amine, and the like). Alternatively,the reaction for generating isocyanate from the compound represented bythe general formula (SM1) and the reaction for reacting the compoundrepresented by the general formula (1-b) may be carried out in theopposite order. Furthermore, the reaction is carried out, for example,in the organic solvent (dichloromethane, N,N-dimethylformamide), in thepresence of 1,1′-carbonylbis-1H-imidazole (CDI), in the presence orabsence of base (triethylamine, N-methyl morpholine, and the like) atabout 0 to 80° C. It is desirable that any of these reactions be carriedout under the atmosphere of inert gas (argon, nitrogen, and the like) inthe anhydrous condition.

Herein, in the reaction scheme 1, deprotection of a hydroxyl group shownin the reaction 2 is carried out if necessary. In the compoundrepresented by the general formula (1-a), when T is R¹, the compoundrepresented by the general formula (1-a) can be produced withoutcarrying out the deprotection reaction.

The deprotection reaction of the protective group for the hydroxyl groupis well known, and can be carried out by the methods mentioned below.Examples thereof include:

(1) a deprotection reaction by alkaline hydrolysis,

(2) a deprotection reaction in acidic conditions,

(3) a deprotection reaction by hydrogenolysis,

(4) a deprotection reaction of a silyl group,

(5) a deprotection reaction using metal,

(6) a deprotection reaction using a metal complex, and the like.

These methods will be specifically described:

(1) The deprotection reaction by alkaline hydrolysis condition iscarried out, for example, in an organic solvent (methanol,tetrahydrofuran, dioxane, and the like) using hydroxide of alkalinemetal (sodium hydroxide, potassium hydroxide, lithium hydroxide, and thelike), hydroxide of alkaline earth metal (barium hydroxide, calciumhydroxide, and the like), or carbonate (sodium carbonate or potassiumcarbonate, and the like), or an aqueous solution thereof or a mixturethereof at temperatures of about 0 to 40° C.

(2) The deprotection reaction in acidic conditions is carried out, forexample, in an organic solvent (dichloromethane, chloroform, dioxane,ethyl acetate, anisole, and the like), in organic acid (acetic acid,trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, andthe like), or inorganic acid (hydrochloric acid, sulfuric acid, and thelike) or a mixture thereof (hydrogen bromide/acetic acid, and the like)at temperatures of about 0 to 100° C.

(3) The deprotection reaction by hydrogenolysis is carried out, forexample, in a solvent (ethers (tetrahydrofuran, dioxane,dimethoxyethane, diethyl ether, and the like), alcohols (methanol,ethanol, and the like), benzenes (benzene, toluene, and the like),ketones (acetone, methyl ethyl ketone, and the like), nitriles(acetonitrile, and the like), amides (dimethylformamide, and the like),water, ethyl acetate, acetic acid, or a mixture of two or more thereof,etc.) in the presence of a catalyst (palladium-carbon, palladium black,palladium hydroxide, platinum oxide, Raney nickel, and the like) underhydrogen atmosphere at normal pressure or elevated pressure, or in thepresence of ammonium formate at temperatures of about 0 to 200° C.

(4) The deprotection reaction of a silyl group is carried out, forexample, in a water-miscible organic solvent (tetrahydrofuran,acetonitrile, and the like), by using tetrabutylammonium fluoride attemperatures of about 0 to 40° C.

(5) The deprotection reaction using metal is carried out, for example,in an acidic solvent (acetic acid, a buffer solution of pH 4.2 to 7.2 ora mixture thereof and an organic solvent such as tetrahydrofuran, andthe like), in the presence of a zinc powder, if necessary undersonication, at temperatures of about 0 to 40° C.

(6) The deprotection reaction using a metal complex is carried out, forexample, in an organic solvent (dichloromethane, dimethylformamide,tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, and thelike), water or a mixture thereof, in the presence of a trap reagent(tributyltin hydride, triethylsilane, dimedone, morpholine,diethylamine, pyrrolidine, and the like), an organic acid (acetic acid,formic acid, 2-ethylhexanic acid, and the like) and/or an organic acidsalt (sodium 2-ethylhexanate, potassium 2-ethylhexanate, and the like),in the presence or absence of a phosphine reagent (triphenylphosphine,and the like), using a metal complex(tetrakis(triphenylphosphine)palladium (O),dichlorobis(triphenylphosphine)palladium (II), palladium acetate (II),chlorotris(triphenylphosphine)rhodium (I), and the like) at temperaturesof about 0 to 40° C.

In addition to the above-mentioned methods, the deprotection reactioncan be carried out by, for example, the method described in “ProtectiveGroups in Organic Synthesis (T. W. Greene, John Wiley&Sons Inc, 1999)”.

As those skilled in the art can easily understand, the objectivecompound of the present invention can be easily produced byappropriately using these deprotection reactions.

A compound in which Y is a bond among the compounds represented by thegeneral formula (I), that is, a compound represented by the generalformula (2-a):

(wherein all of the symbols represent the same meanings as mentionedabove) can be produced by a method shown in the reaction scheme 2:

(wherein all of the symbols represent the same meanings as mentionedabove).

That is to say, the objective compound can be produced by subjecting thecompound represented by the general formula (SM1) and the compoundrepresented by the general formula (2-b) to the reaction 3: amidationreaction, and to the reaction 4: deprotection reaction of a hydroxylgroup if necessary.

The amidation reaction is well known, and examples thereof include:

(1) a method using an acid halide,(2) a method using a mixed acid anhydride, and(3) a method using a condensing agent.These methods are specifically described below:

(1) The method using an acid halide is carried out, for example, byreacting a carboxylic acid with an acid halogenating agent (oxalylchloride, thionyl chloride, and the like) in an organic solvent(chloroform, dichloromethane, diethyl ether, tetrahydrofuran, and thelike) or in the absence of any solvent at −20° C. to reflux temperature,and then reacting the obtained acid halide with an amine in the presenceof a base (pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, diisopropylethylamine, and the like) in anorganic solvent (chloroform, dichloromethane, diethyl ether,tetrahydrofuran, and the like) at 0 to 40° C. Furthermore, the methodcan be also carried out by reacting the obtained acid halide with anamine, at 0 to 40° C. by using an alkaline aqueous solution (sodiumbicarbonate water or a sodium hydroxide solution, and the like) in anorganic solvent (dioxane, tetrahydrofuran, and the like).

(2) The method using a mixed acid anhydride is carried out, for example,by reacting carboxylic acid with an acid halide (pivaloyl chloride,tosyl chloride, mesyl chloride, and the like) or an acid derivative(ethyl chloroformate, isobutyl chloroformate, and the like) in anorganic solvent (chloroform, dichloromethane, diethyl ether,tetrahydrofuran, and the like) or in the absence of any solvent in thepresence of a base (pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, diisopropylethylamine, and the like) at 0 to 40°C., and then reacting the obtained mixed acid anhydride with an amine inan organic solvent (chloroform, dichloromethane, diethyl ether,tetrahydrofuran, and the like) at 0 to 40° C.

(3) The method using a condensing agent is carried out, for example, byreacting a carboxylic acid with an amine in an organic solvent(chloroform, dichloromethane, dimethyl formamide, diethyl ether,tetrahydrofuran, and the like) or in the absence of any solvent in thepresence or absence of a base (pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, and the like), using a condensing agent(1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonylbis-1H-imidazole (CDI), 2-chloro-1-methylpyridinium iodine,1-propylphosphonic acid cyclic anhydride (1-propanephosphonic acidcyclic anhydride, PPA), and the like), and in the presence or absence of1-hydroxybenztriazole (HOBt) at 0 to 40° C.

These reactions (1), (2), and (3) are desirably carried out under theatmosphere of an inert gas (argon, nitrogen, and the like) in anhydrousconditions.

Herein, deprotection of a hydroxyl group is carried out if necessary. Inthe compound represented by the general formula (2-a), when T is R¹, thecompound represented by the general formula (2-a) can be producedwithout carrying out the deprotection reaction.

The deprotection reaction of a hydroxyl group can be carried out in thesame manner as in the deprotection reaction of a hydroxyl groupdescribed in the reaction scheme 1.

The compound represented by the general formula (SM1) can be producedusing the compound represented by the general formula (3-a):

(wherein W represents halogen (Cl, Br, I) or a Tf(trifluoromethanesulphonyl) O group, or a Ts (toluenesulphonyl) O group,R⁴¹ and R⁵¹ each represent the same meaning as those of R⁴ and R⁵(wherein, both R⁴¹ and R⁵¹ may be simultaneously a hydrogen atom), andthe other symbols represent the same meanings as mentioned above); andthe compound represented by the general formula (3-b):

(wherein all of the symbols represent the same meanings as mentionedabove), orthe compound represented by the general formula (3-g):

(wherein X represents halogen (Cl, Br, I), R¹⁰⁰ and R¹¹⁰ eachindependently represent a hydrogen atom or a protective group of anamino group, the other symbols represent the same meanings as mentionedabove), as starting materials, by a method shown in the reaction scheme3:

(wherein all of the symbols represent the same meanings as mentionedabove).

The compounds represented by the general formula (3-a) in which W is aTfO group or a TsO group, can be produced from a compound in which W isa hydroxyl group by a well-known method, for example, the methoddescribed in “Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, second edition (Richard C. Larock, JohnWiley & Sons Inc, 1999)” and the like. Furthermore, they can be producedby the method described in Example 37.

Examples of the protective group for an amino group in R¹⁰⁰ and R¹¹⁰include a benzyloxycarbonyl group, a tert-butoxycarbonyl (Boc) group, anallyloxycarbonyl (Alloc) group, a 1-methyl-1-(4-biphenyl)ethoxycarbonyl(Bpoc) group, a trifluoroacetyl group, a 9-fluororenylmethoxycarbonylgroup (Fmoc), a benzyl (Bn) group, a p-methoxybenzyl group, abenzyloxymethyl (BOM) group, a 2-(trimethylsilyl)ethoxymethyl (SEM)group, and the like.

The protective groups are not particularly limited to theabove-described groups, and may include, in addition to theabove-mentioned groups, groups that can be detached easily andselectively. For example, those described in “Protective Groups inOrganic Synthesis (T. W. Greene, John Wiley & Sons Inc, 1999)” may beused.

In the reaction scheme 3, the nucleophilic reaction shown in thereactions 5 and 6 is carried out by reacting the compound represented bythe general formula (3-a) or the general formula (3-b) with an organicmetal reagent corresponding to R³, for example, alkyl (R³) magnesiumbromide, alkyl (R³) lithium in an organic solvent (tetrahydrofuran,diethyl ether, and the like) in the presence or absence of ceriumchloride at temperatures from −78° C. to room temperature. Furthermore,the reaction is carried out also by reacting Rupert reagent(trifluoromethyl trimethyl silane) in the organic solvent(tetrahydrofuran, diethyl ether, and the like) in the presence oftetrabutyl ammonium fluoride at temperatures from −78° C. to roomtemperature.

In the reaction scheme 3, the reduction reaction shown in the reactions5 and 6 is carried out by reacting the compound represented by thegeneral formula (3-a) (wherein R² is other than hydrogen) with areducing agent (sodium borohydride, lithium borohydride, lithiumaluminum hydride, diisobutylaluminium hydride, and the like) in anorganic solvent (methanol, ethanol, tetrahydrofuran, hexane, and thelike) at temperatures from −78° C. to 80° C.

In the reaction scheme 3, the amination reaction shown in the reaction 7is carried out by reacting the compound represented by the generalformula (3-c) and the compound represented by the general formula (3-d)at temperatures from room temperature to −120° C., in an organic solvent(ethyl acetate, isopropyl acetate, benzene, toluene, xylene, heptane,cyclohexane, tetrahydrofuran, dioxane, dimethoxyethane, ethanol,isopropanol, polyethylene glycol, dimethyl sulfoxide,N,N-dimethylformamide, N,N-dimethyl acetamide, N-methyl-2-pyrrolidinone,methylene chloride, chloroform, acetone, acetonitrile, water, or themixture thereof, or the like), in the presence of base (diethylamine,triethylamine, propyl amine, diisopropyl amine, diisopropyl ethyl amine,dibutyl amine, tributyl amine, pyrrolidine, piperidine, N-methylpiperidine, 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine, sodiumhydroxide, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, cesium carbonate, sodium phosphate, potassium phosphate,potassium fluoride, or the like), and a catalyst (palladium catalyst(for example, tetrakis(triphenylphosphine) palladium (Pd(PPh₃)₄),bis(triphenylphosphine)palladium dichloride (PdCl₂(PPh₃)₂), palladiumacetate (Pd(OAc)₂), palladium dichloride (PdCl₂), palladium black,1,1′-bis(diphenylphosphino ferrocene)dichloropalladium (PdCl₂(dppf)₂),diallyl dichloride palladium (PdCl₂(allyl)₂),phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh₃)₂),tris(dibenzylideneacetone)dipalladium (Pd₂(DBA)₃), bis(tri-tert-butylphosphine)palladium (Pd(tBu₃P)₂), and the like), and in the presence ofligand (for example, 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene,and the like).

In the reaction scheme 3, the halogen-metal exchange reaction of arylhalide, and subsequent nucleophilic reaction shown in reaction 8 arecarried out by reacting the compound represented by the general formula(3-g) with an organic metal reagent (n-butyllithium, tert-butyllithium,isopropylmagnesium bromide, isopropylmagnesium chloride) in an organicsolvent (tetrahydrofuran, diethyl ether, and the like) at temperaturesfrom −78 to 60° C., and then reacting the compound represented by thegeneral formula (3-h) in an organic solvent (tetrahydrofuran, diethylether, and the like) at temperatures from −78 to 60° C.

In the reaction scheme 3, protection reactions of a hydroxyl group shownin the reactions 9, 12, and 14 are carried out if necessary. Theprotection reaction is carried out by, for example, reacting thecompounds represented by the general formulae (3-e), (3-f), and (3-k)with a silylating agent (chlorotrimethylsilane, chlorotriethylsilane,chloro-tert-butyl dimethylsilane, chloro-tert-butyl diphenylsilane, andthe like) in an organic solvent (tetrahydrofuran, dichloromethane, andthe like) in the presence of a base (imidazole, triethylamine, and thelike) at temperatures from 0° C. to room temperature.

The protective groups are not particularly limited to theabove-described groups, and may include, in addition to theabove-mentioned groups, groups that can be detached easily andselectively. For example, those described in “Protective Groups inOrganic Synthesis (T. W. Greene, John Wiley & Sons Inc, 1999)” may beused.

In the reaction scheme 3, the reduction reactions of a nitro group shownin the reactions 10 and 13 are carried out with respect to the compoundrepresented by the general formula (3-e) or (3-i) in a solvent (ethers(tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, and thelike), alcohols (methanol, ethanol, and the like), benzenes (benzene,toluene, and the like), ketones (acetone, methyl ethyl ketone, and thelike), nitriles (acetonitrile, and the like), amides (dimethylformamide,and the like), water, ethyl acetate, acetic acid, or a mixture of two ormore thereof, etc.) in the presence of a catalyst (palladium-carbon,palladium black, palladium hydroxide, platinum oxide, Raney nickel,etc.) under hydrogen atmosphere at normal pressure or elevated pressure,or in the presence of ammonium formate at temperatures of about 0 to200° C. Alternatively, the reaction is carried out using a metal reagent(zinc, iron, tin, tin chloride, iron chloride, samarium, indium, sodiumborohydride-nickel chloride and the like) in a water-miscible solvent(ethanol, methanol, tetrahydrofuran, and the like), in the presence orabsence of acids (hydrochloric acid, hydrobromic acid, ammoniumchloride, acetic acid, ammonium formate, and the like) at temperaturesof about 0 to 150° C.

In the reaction scheme 3, the deprotection reaction of an amino groupshown in the reactions 11 and 15 can be carried out by the followingmethod.

The deprotection reaction of an amino group is well known, and can becarried out by the methods mentioned below. Examples thereof include:

(1) a deprotection reaction by alkaline hydrolysis,

(2) a deprotection reaction in acidic conditions,

(3) a deprotection reaction by hydrogenolysis,

(4) a deprotection reaction of a silyl group,

(5) a deprotection reaction using metal,

(6) a deprotection reaction using a metal complex, and the like.

These deprotection reaction can be carried out in the same manner as inthe deprotection of a hydroxyl group described above.

The protective groups are not particularly limited to theabove-described groups, and may include, in addition to theabove-mentioned groups, groups that can be detached easily andselectively. For example, those described in “Protective Groups inOrganic Synthesis (T. W. Greene, John Wiley & Sons Inc, 1999)” may beused.

Herein, in the compound represented by the general formula (3-n), whenany one of R⁴¹ and R⁵¹ is a hydrogen atom, if necessary, or when both ofR⁴¹ and R⁵¹ are simultaneously a hydrogen atom, the compound representedby the general formula (3-n) is subjected to the halogenation reactionshown in the reaction 16.

In the reaction scheme 3, the halogenation reaction shown in thereaction 16 is carried out by reacting the compound represented by thegeneral formula (3-n) with a halogenation reagent (N-chlorosuccinimide,1,3-dichloro-5,5-dimethylhydantoin, N-bromosuccinimide,N-iodosuccinimide, and the like) in an organic solvent (acetonitrile,N,N-dimethylformamide, and the like) at temperatures from 0 to 80° C.

A compound represented by the general formula (I) in which R¹¹ is NH₂,and Y is —NH— or —O—, that is, a compound represented by the generalformula (4-a) (wherein Y₁ is —NH— or —O—, the other symbols representthe same meanings as mentioned above) can be produced by a method shownin the reaction scheme 4 (wherein all of the symbols represent the samemeanings as mentioned above) using the compound represented by thegeneral formula (SM2).

In the reaction scheme 4, the reaction to form urea, or the reaction toform urethane shown in the reaction 17 can be carried out by the samemethod as in the reaction 1 described in the reaction scheme 1 above.

In the reaction scheme 4, the reduction reaction of an azide group shownin the reaction 18 is carried out by reacting triphenylphosphine in amixed solvent of an organic solvent (tetrahydrofuran, dimethyl ethylether, and the like) and water at room temperature. Furthermore, thereaction is also carried out by reacting lithium aluminum hydride in theorganic solvent (tetrahydrofuran, and the like) while heating andrefluxing from 0° C.

A compound represented by the general formula (I) in which R¹¹ is NH₂,and Y is a bond, that is, a compound represented by the general formula(5-a) (wherein all of the symbols represent the same meanings asmentioned above) can be produced by a method shown in the reactionscheme 5 (wherein all of the symbols represent the same meanings asmentioned above) using the compound represented by the general formula(SM2).

In the reaction scheme 5, the amidation reaction shown by the reaction19 can be carried out by the same method as in the reaction 3 describedin the reaction scheme 2 described above.

In the reaction scheme 5, the reduction reaction shown by the reaction20 can be carried out by the same method as in the reaction 18 describedin the reaction scheme 4 above.

The compound represented by the general formula (SM2) can be produced bythe method shown by the reaction scheme 6 (wherein all of the symbolsrepresent the same meanings as mentioned above) using the compoundrepresented by general formula (SM1) as a starting material.

In the reaction scheme 6, the deprotection reaction of a hydroxyl groupshown by the reaction 21 can be carried out in the same manner as in thedeprotection reaction of a hydroxyl group shown by the reaction scheme 1above.

In the reaction scheme 6, the conversion reaction of a hydroxyl groupinto an azide group is carried out by reacting the compound representedby the general formula (6-a) with sodium azide or potassium azide in anorganic solvent (chloroform, dichloromethane, and the like), in thepresence of trifluoroacetic acid, at room temperature. Furthermore, thereaction is also carried out by reacting diphenyl phosphorazidate and2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine in the organic solvent(toluene, tetrahydrofuran, and the like) at temperatures from 0° C. toroom temperature.

An optically active substance of the compound represented by the generalformula (I) can be produced by a routine procedure (for example, anoptical resolution method using a chiral column, and the like).Furthermore, the optically active substance of the compound representedby the general formula (I) can also be produced by the method shown inthe above reaction scheme by using the optical isomer of the compoundsrepresented by the general formulae (3-c), (3-e), (3-f), (3-i), (3-k),(3-m), (3-n), (SM1), (4-b), (5-b), (6-a), and (SM2) separated in advanceby an optical resolution method such as a routine procedure (forexample, an optical resolution method using a chiral column, and thelike) or the method described in the Examples of the presentspecification.

In each reaction of the present specification, the compounds representedby the general formulae (1-b), (2-b), (3-a), (3-b), (3-d), (3-g), and(3-h) used as a starting material or a reagent are well-known in itself,or can be easily produced by Examples described in the presentspecification or by a well-known methods.

In each reaction in the present specification, as is apparent to askilled person in the art, the reactions involving heating can becarried out using a water bath, an oil bath, a sand bath or a microwave.

In each reaction in the present specification, a solid-supported reagentwhich is supported on a high molecular polymer (for example,polystyrene, polyacrylamide, polypropylene, polyethylene glycol, and thelike) may be appropriately used.

In each reaction in the present specification, reaction products can bepurified by usual purification methods, for example, by distillation atnormal or reduced pressure, by high performance liquid chromatographyusing silica gel or magnesium silicate, thin layer chromatography,ion-exchange resin, scavenger resin, or column chromatography, orwashing, recrystallization, or the like. The purification may be carriedout after each reaction or after several reactions.

[Toxicity]

The compound of the present invention has sufficiently low toxicity, andcan be safely used as pharmaceuticals.

[Application to Pharmaceuticals]

The compound of the present invention is suitable for preventing and/ortreating KCNQ2-5 channel-related diseases.

The compound of the present invention can be used for preventing and/ortreating KCNQ2-5 channel-related diseases. Examples of the diseasesinclude epilepsy, pain disorders (for example, neurogenic pain, andmigraine), diabetic peripheral nerve disorders, anxiety disorder, moodadjustment disorders, schizophrenic disorder, drug dependence, attentionadjustment disorders, sleep disorders, cerebral stroke, tinnitus, memorydisorders (for example, Alzheimer's disease, and dementia), amyotrophiclateral sclerosis, movement disorders (for example, Parkinson's disease,and dystonia-related movement disorder), dysuria (for example,overactive urinary bladder, urinary frequency, nocturia, urinaryurgency, urge urinary incontinence, stress urinary incontinence,interstitial cystitis, chronic prostatitis, and benign prostatichypertrophy), hardness of hearing, asthma, chronic obstructive pulmonarydisease, coughing, pulmonary hypertension, neurodegenerative disease ofvisual organ (for example, glaucoma, progressive diabetic retinopathy,maculopathy with aging, retinal pigmentary degeneration), DiabetesMellitus, and the like.

The compound of the present invention is suitable for preventing and/ortreating preferably dysuria.

The compound of the present invention is suitable for preventing and/ortreating more preferably overactive urinary bladder.

The overactive urinary bladder is symptoms syndromes involving certainlyurinary urgency, usually urinary frequency and nocturia, and sometimesurine incontinence.

When the compound of the present invention is used for preventing and/ortreating dysuria, in order to avoid central nervous system adverseeffects such as dizziness and sleepiness, it is preferable that theintracerebral migration of the compound of the present invention is low.Therefore, the compound of the present invention is preferably acompound having the reduced intracerebral migration. The intracerebralmigration can be evaluated by, for example, intracerebral content or thecalculated intracerebral migration rate (intracerebral content/plasmaconcentration) obtained by administering a test substance to mammals(for example, rat and mouse) by oral administration or intravenousadministration, and measuring the plasma concentration and/or theintracerebral content after the administration (for example, one hourafter the administration).

The compound of the present invention may be administered as acombination drug in combination with other drugs in order to accomplishthe following purposes:

1) to supplement and/or enhance the preventive and/or therapeuticeffect;2) to improve the kinetics, improvement of absorption, and to reduce thedose; and/or3) to eliminate the adverse effects.

A combination drug of the compound of the present invention and one ormore of other drugs may be administered in the form of a compoundingagent including all the components mixed into one formulation, or may beadministered in separate formulations. Administration as separateformulations includes simultaneous administration and administration atdifferent times. In the administration at different times, the compoundof the present invention may be administered before the other drug.Alternatively, the other drug may be administered before the compound ofthe present invention. The method for the administration of these drugsmay be the same as or different from each other.

Diseases on which the preventive and/or therapeutic effect of theabove-mentioned combination drug works are not particularly limited butmay be those in which the preventive and/or therapeutic effect of thecompound of the present invention is supplemented and/or enhanced.

Examples of other drugs to supplement and/or enhancement for preventiveand/or therapeutic effect for overactive urinary bladder by the compoundof the present invention include: (1) muscarinic receptor antagonists(for example, tolterodine, oxybutynin, hyoscyamine, propantheline,propiverine, trospium, solifenacin, dalifenacin, imidafenacin,fesoterodine, temiverine, flavoxate, tarafenacin, afacifenacin,THVD-101, THVD-201, and the like), (2) β3 adrenergic receptor agonist(Mirabegron, KRP-114V, Solabegron, TRK-380, and the like), (3) NK-1 or-2 antagonist (for example, aprepitant, cizolirtine, and the like), (4)genetically modified botulinus toxin (senrebotase, and the like), (5)opioid μ receptor agonist (TRK-130 or the like), (6) α4β2 nicotinicacetylcholine receptor antagonist (dexmecamylamine or the like), (7)C-fiber inhibitor (Besipirdine, or the like), (8) TRPV1 antagonist(XEN-D0501, or the like), (9) EP1 antagonist (KEA-0447, or the like),(10) central nervous system drug (REC-1819, or the like), (11) α1adrenergic receptor antagonist (for example, Tamsulosin, Silodosin,Naftopidil, Urapidil, and the like), (12) 5α reductase inhibitor(Dutasteride, finasteride, and the like), (13) phosphodiesterase 5inhibitor (Sildenafil, Tadalafil, Vardenafil), (14) vasopressinV2receptor agonist (desmopressin), or the like.

A dosage of the other drugs can be appropriately selected on the basisof the clinical dose. Further, a mixing proportion of the compound ofthe present invention and the other drugs can be appropriately selectedon the basis of age and body weight of a subject, medication method,administration period, disease, symptoms or combination thereof, and thelike. For example, 0.01 to 100 parts by mass of the other drugs for onepart by mass of the compound of the present invention may be used. Anytwo or more other drugs may be administered in combination at a suitableproportion. Furthermore, the other drugs include not only drugs whichhave been found to date but also drugs that will be found in the future.

When the compound of the present invention or combination agents of thecompound of the present invention and other agents are used for theabove-mentioned purposes, they are usually administered systemically orlocally, usually by oral or parenteral administration after, usually,they are formulated together with pharmaceutically acceptable carrier inan appropriate pharmaceutical composition.

The compound of the present invention is administered to mammal(preferably, human, and more preferably, patient) in an effectiveamount.

Since doses of the compound of the present invention are dependent onages, body weight, symptoms, desired therapeutic effect, administrationroute, treatment time, and the like, it inevitably varies. The doses perpatient are generally from 0.1 mg to 1000 mg per dose, once to severaltimes per day, by oral administration, or from 0.01 mg to 100 mg perdose, once or several times per day, by parenteral administration, orcontinuous administration for 1 to 24 hours per day intravenously.

Needless to say, as mentioned above, the doses to be used vary dependentupon various conditions. Therefore, doses lower than the rangesspecified above may be sufficient in some cases, and doses higher thanthe ranges specified above are needed in some cases.

When the compound of the present invention or the combined preparationof the compound of the present invention and other pharmaceutical isadministered, it is used as internal solid composition and internalliquid composition for oral administration, sustained releasepreparation and controlled release preparation for oral administration,and injection, external preparation, inhalant, suppository forparenteral administration, or the like.

Examples of the internal solid composition for oral administrationincludes tablets, pills, capsules, powder and granules. The capsulesinclude hard capsules and soft capsules.

In such a solid composition, one or more active substance(s) is used byitself or by being mixed with vehicle (for example, lactose, mannitol,glucose, microcrystalline cellulose, and starch, and the like), bindingagent (for example, hydroxypropylcellulose, polyvinyl pyrrolidone, andmagnesium aluminometasilicate, and the like), disintegrator (forexample, calcium carboxymethylcellulose and the like), lubricant (forexample, magnesium stearate and the like), stabilizer, a dissolution aid(for example, glutamic acid, aspartic acid, and the like), and the like,and being pharmaceutically manufactured by a conventional method. Thesolid composition may be coated with coating (for example, saccharose,gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulosephthalate, and the like), if necessary, or may be coated with two ormore layers. Capsule of a substance that can be absorbed, such asgelatin, is also included.

The internal liquid composition for oral administration includespharmaceutically acceptable solution, suspension, emulsum, syrup andelixir, and the like. In the liquid composition, one or more activesubstance(s) is dissolved, suspended or emulsified in a commonly usedinert diluent (for example, purified water, ethanol or the mixturethereof, and the like). The composition may contain humectant,suspending agent, emulsifying agent, sweetener, flavor, aromatic agent,preservative and buffer, and the like.

Furthermore, the sustained release preparation in oral administration isalso effective. A gel formation substance to be used for these sustainedrelease preparation is a substance that is swelled by including asolvent, the colloid particles thereof are linked to each other to forma three-dimensional network structure, and can form a jelly-likesubstance which has lost fluidity. In preparation, it is mainly used asa binding agent, a thickener, and sustained release base material. Forexample, gum arabic, agar, polyvinyl pyrrolidone, sodium alginate,propylene glycol alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose, guar gum, gelatin,hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylalcohol, methyl cellulose, or hydroxyethyl methyl cellulose, can beused.

The injection agents for parenteral administration include solutions,suspensions, emulsions and solid injection agents to be dissolved in asolvent before use. The injection agent is used by dissolving,suspending or emulsifying one or more active substance(s) in a solvent.Examples of the solvent include distilled water for injection,physiological saline, vegetable oils, alcohols such as propylene glycol,polyethylene glycol, ethanol, and mixtures thereof. Furthermore, theinjection agent may contain a stabilizer, a dissolution aid (glutamicacid, aspartic acid, and Polysorbate 80 (registered trademark), and thelike), a suspending agent, an emulsifying agent, a soothing agent, abuffer, a preservative, and the like. Such an injection agent isproduced by sterilizing at the final step or employing an asepticprocess. Furthermore, it is also possible to employ as an aseptic solidproduct (for example, produced freeze-dried product is dissolved indistilled water for injection or other solvent, wherein the saiddistilled water for injection or other solvent are aseptic or aresterilized before use).

Examples of the external preparation for parenteral administrationincludes a nebulizer, an inhalant, a spray agent, an aerosol agent,ointments, gels, creams, poultices, plasters, liniments, and nasalagents. These may contain one or more active substance(s) and may beprepared by well-known methods or conventional methods.

The nebulizer, an inhalant, and a spray agent may contain a stabilizersuch as sodium hydrogen sulfite, a buffer agent that providesisotonicity, and an isotonic agent, for example, sodium chloride, sodiumcitrate, or citric acid, other than a generally used diluent. The methodfor producing a spray agent is described in detail in, for example, U.S.Pat. No. 2,868,691 and No. 3,095,355.

The inhalation agent for parenteral administration includes aerosolpreparation, powder for inhalation and liquid for inhalation. The liquidfor inhalation may be a form such as the ingredient is dissolved orsuspended in water or in other appropriate medium at time of use.

Those inhalation agents are prepared according to well-known methods.

For example, in the case of liquid for inhalation, an antiseptic agent(for example, benzalkonium chloride, paraben, and the like), a coloringagent, a buffer (for example, sodium phosphate, sodium acetate, and thelike), an isotonizing agent (for example, sodium chloride, concentratedglycerol, and the like), a thickener (carboxyvinyl polymer and thelike), an absorption promoter, and the like, are appropriately selectedand prepared if necessary.

In the case of powder for inhalation, lubricant (for example, stearicacid, salt thereof, and the like), a binder (for example, starch,dextrin, and the like), an excipient (for example, lactose, cellulose,and the like), a coloring agent, antiseptic (for example, benzalkoniumchloride or paraben, and the like), or absorption promoter, and thelike, are appropriately selected and prepared if necessary.

In the administration of the liquid for inhalation, a spraying device(for example, atomizer, nebulizer, or the like) is usually used. In theadministration of the powder for inhalation, an administering device forinhalation of powdery pharmaceutical is usually used.

An ointment is produced by well-known methods or generally usedprescriptions. For example, an ointment is produced by mixing or meltingof one or more active substance(s) into base material. The ointment basematerial is selected from well-known material or generally usedmaterial. For example, a single material or a mixture of two or more ofmaterials are selected from higher fatty acids and higher fatty acidesters (for example, adipic acid, myristic acid, palmitic acid, stearicacid, oleic acid, adipate esters, myristate esters, palmitate esters,stearate esters, and oleate esters), waxes (for example, beeswax,spermaceti, and ceresin), surfactants (for example, polyoxyethylenealkyl ether phosphate esters), higher alcohols (for example, cetanol,stearyl alcohol, and cetostearyl alcohol), silicone oils (for example,dimethylpolysiloxane), hydrocarbons (for example, hydrophilicpetrolatum, white petrolatum, purified lanolin, and liquid paraffin),glycols (for example, ethylene glycol, diethylene glycol, propyleneglycol, polyethylene glycol, and macrogol), plant oils (for example,castor oil, olive oil, sesame oil, and turpentine oil), animal oils (forexample, mink oil, egg yolk oil, squalane, and squalene), water,absorption promoters, and anti-rash agents. Furthermore, a humectant,preservative, stabilizer, anti-oxidant, an aromatizing agent, and thelike, may be included.

The gel is prepared by well-known methods or usually used methods. Forexample, it may be prepared by melting one or more active substance(s)into a base. The gel base is chosen from well-known or usually usedones. For example, it is used by mixing with one or more base(s) chosenfrom lower alcohol (for example, ethanol and isopropyl alcohol, and thelike), gelatinizer (for example, carboxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose or ethylcellulose, etc.),neutralizer (for example, triethanolamine or diisopropanolamine, etc.),surfactant (for example, polyethylene glycol monostearate etc.), gums,water, absorption promoter and anti-rash agents. Further, it may includepreservative, anti-oxidant or flavor, etc.

The cream is prepared by known or commonly used formulation. Forexample, a cream is produced by melting or emulsifying one or moreactive substance(s) in a base. The cream base is selected from known orcommonly used bases. Examples of the cream base include higher fattyacid esters, lower alcohols, hydrocarbons, polyhydric alcohols (such aspropylene glycol and 1,3-butylene glycol), higher alcohols (such as2-hexyldecanol and cetanol), emulsifying agents (such as polyoxyethylenealkyl ethers and fatty acid esters), water, absorption enhancers, andanti-rash agents. From these bases, one base is selected and used singlyor two or more bases are selected and used in admixture. The cream mayfurther contain a preservative, an anti-oxidant, an aromatizing agent,or the like.

The poultice is produced according to a known or commonly usedformulation. For example, a poultice is produced by melting one or moreactive substance(s) in a base to form a kneaded material, followed byapplying and spreading the kneaded material on a support. The poulticebase is selected from known or commonly used bases. Examples of thepoultice base include viscosity increasing agents (for example,polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, andmethyl cellulose), humectants (for example, urea, glycerin, andpropylene glycol), fillers (for example, kaolin, zinc oxide, talc,calcium, and magnesium), water, dissolution aids, tackifiers, andanti-rash agents. From these bases, one base is selected and used singlyor two or more bases are selected and used in admixture. The poulticemay further contain a preservative, an anti-oxidant, an aromatizingagent, or the like.

The plaster is produced according to a known or commonly usedformulation. For example, a plaster is produced by melting one or moreactive substance(s) in a base and applying and spreading the melt on asupport. The plaster base is selected from known or commonly used bases.Examples of the plaster base include polymeric bases, oils and fats,higher fatty acids, tackifiers, and anti-rash agents. From these bases,one base is selected and used alone or two or more bases are selectedand used in admixture. The plaster may further contain a preservative,an antioxidant, an aromatizing agent, or the like.

The liniment is produced according to a known or commonly usedformulation. For example, a liniment is prepared by dissolving,suspending, or emulsifying one or more active substances in one or morematerials selected from water, an alcohol (for example, ethanol orpolyethylene glycol), a higher fatty acid, glycerin, a soap, anemulsifying agent, and a suspending agent. The liniment may furthercontain a preservative, an anti-oxidant, an aromatizing agent, or thelike.

Examples of the other compositions for parenteral administration includesuppositories for intrarectal administration, pessaries for intravaginaladministration, and the like, each containing one or more activesubstance(s) and formulated according to routine procedure.

The entire contents of all Patent Literature and Non Patent Literatureor Reference Literature explicitly cited in this description can beincorporated herein by reference as a part of this description.

EXAMPLES

Hereinafter, the present invention will be described in detail byExamples. However, the present invention is not limited to the Examples.

The solvents in the parenthesis indicated in the separated portion bythe chromatography and TLC represent eluting or developing solvents usedand their ratio is volume ratio.

In the present invention, for column chromatography on silica gel,CHROMATOREX (registered trademark) manufactured by Fuji Silysia ChemicalLTD., Yamazen High flash column (product name) and the like were used,as a purifier, for example, a medium-pressure preparative liquidchromatograph, W-prep 2XY (product name) manufactured by YamazenCorporation was used.

NMR data is the data of ¹H-NMR unless otherwise stated.

Inside parentheses of NMR represents a solvent used for measurement.

Name of the compounds used in the present specification are named byusing ACD/Name (registered trademark) manufactured by Advanced ChemistryDevelopment Inc., which is a computer program for naming compoundsaccording to the regulation of IUPAC, or named according to the namingmethod of IUPAC.

In the present invention, retention time of an analysis by liquidchromatography (LC) was measured by using the following instruments andin the following conditions.

Analyzer: ACQUITY UPLC I-Class system (manufactured by Waters)

Detector: UV (PDA), ELSD, MS Condition 1

Column: ACQUITY UPLC BEH C18 Column (manufactured by Waters, 1.7 μm, 2.1mm×30 mm)

Mobile phase: Liquid A: 0.1% formic acid aqueous solution; Liquid B:0.1% formic acid-acetonitrile solution

Gradient: 0 min (Liquid A/Liquid B=95/5); 0.1 min (Liquid A/LiquidB=95/5); 1.2 min (Liquid A/Liquid B=5/95); 1.4 min (Liquid A/LiquidB=5/95); 1.5 min (Liquid A/Liquid B=95/5)

Flow rate: 1 mL/min,

Detection method: 254 nm,

Column temperature: 30° C.,

Filling amount: 2 μL

Condition 2

Column: ACQUITY UPLC BEH C18 Column (manufactured by Waters, 1.7 μm, 2.1mm×30 mm)

Mobile phase: Liquid A: 0.1% trifluoroacetic acid aqueous solution;Liquid B: 0.1% trifluoroacetic acid-acetonitrile solution

Gradient: 0 min (Liquid A/Liquid B=95/5); 0.1 min (Liquid A/LiquidB=95/5); 1.2 min (Liquid A/Liquid B=5/95); 1.4 min (Liquid A/LiquidB=5/95); 1.5 min (Liquid A/Liquid B=95/5)

Flow rate: 1 mL/min,

Detection method: 254 nm,

Column temperature: 30° C.,

Filling amount: 2 μL

Condition 3

Column: YMC Triart C18 (manufactured by YMC, 1.9 μm, 2.1 mm×30 mm)

Mobile phase: Liquid A: 0.1% trifluoroacetic acid aqueous solution;Liquid B: 0.1% trifluoroacetic acid-acetonitrile solution

Gradient: 0 min (Liquid A/Liquid B=95/5); 0.1 min (Liquid A/LiquidB=95/5); 1.2 min (Liquid A/Liquid B=5/95); 1.4 min (Liquid A/LiquidB=5/95); 1.5 min (Liquid A/Liquid B=95/5)

Flow rate: 1 mL/min,

Detection method: 254 nm,

Column temperature: 30° C.,

Filling amount: 2 μL

Example 1 1,1,1-trifluoro-2-(4-nitrophenyl)-2-propanol

To a tetrahydrofuran solution (16 mL) of 1-(4-nitrophenyl)ethanone (1.65g) (CAS registry number: 100-19-6) and (trifluoromethyl)trimethylsilane(4.26 g), tetrabutyl ammonium fluoride (1 M tetrahydrofuran solution, 1mL) was added under ice-cooling. The resulting solution was stirred atroom temperature for two hours. A saturated ammonium chloride aqueoussolution was added to the reaction mixture, followed by extraction withethyl acetate. The organic layer was washed sequentially with water andsaturated brine, and dried over anhydrous sodium sulfate, followed byconcentration under reduced pressure. The resulting residue wasdissolved in tetrahydrofuran (16 mL), and tetrabutyl ammonium fluoride(1 M tetrahydrofuran solution, 12 mL) was added thereto underice-cooling. The reaction mixture was stirred for ten minutes underice-cooling, and then concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=85:15→80:20) to obtain the title compound (2.28 g)having the following physical property values.

TLC: Rf 0.47 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 1.83-1.84, 7.78-7.81, 8.23-8.28.

Example 2 2-(4-aminophenyl)-1,1,1-trifluoro-2-propanol

The compound (2.28 g) produced in Example 1 was suspended in ethanol (50mL) and water (10 mL), and powder zinc (3.17 g) and acetic acid (2.82mL) were added thereto. The reaction mixture was stirred over night at50° C. The reaction mixture was cooled to room temperature. A saturatedsodium hydrogencarbonate aqueous solution was added to the mixture, andthe resulting mixture solution was stirred for 30 minutes. To thereaction mixture, ethyl acetate was added. The resulting mixture wasfiltered through a Celite (product name), and the filtrate was extractedwith ethyl acetate. The organic layer was washed with saturated brine,was dried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=80:20→20:80) toobtain the title compound (1.20 g) having the following physicalproperty values.

TLC: Rf 0.37 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 1.72-1.73, 2.32, 6.65-6.70, 7.33-7.35.

Example 3 2-(4-amino-3,5-dichlorophenyl)-1,1,1-trifluoro-2-propanol

To an N,N-dimethylformamide solution (12 mL) of the compound (1.20 g)produced in Example 2, N-chlorosuccinimide (1.56 g) was added, and theresulting solution was stirred at room temperature for 15 hours. Waterwas added to reaction mixture, followed by extraction with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,and then concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (hexane:ethylacetate=80:20→40:60) to obtain the title compound (867 mg) having thefollowing physical property values.

TLC: Rf 0.72 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 1.72-1.73, 2.40, 7.39.

Example 42,6-dichloro-4-{1,1,1-trifluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

To a tetrahydrofuran solution (17 mL) of the compound (860 mg) producedin Example 3, imidazole (1.07 g) and chlorotrimethylsilane (2 mL) wereadded. The reaction mixture was stirred at room temperature for 2.5hours, and water was added thereto, followed by extraction with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by column chromatography on silica gel(hexane:ethyl acetate=100:0→60:40) to obtain the title compound (1.05 g)having the following physical property values.

TLC: Rf 0.68 (hexane:ethyl acetate=8:1);

¹H-NMR (CDCl₃): δ 0.15, 1.74-1.75, 4.51, 7.33.

Example 51-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

To a tetrahydrofuran solution (9.5 mL) of the compound (475 mg) producedin Example 4, N,N-diisopropyl ethyl amine (261 μL) and triphosgene (447mg) were added. The reaction mixture was stirred at room temperature for2.5 hours, followed by concentration under reduced pressure. Theresulting residue was dissolved in tetrahydrofuran (1.4 mL), and1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride (583 mg)(CAS registry number: 164341-39-3) and triethylamine (401 μL) were addedto the resulting mixture. The resulting mixture was stirred at roomtemperature overnight. Water was added to the reaction mixture, followedby extraction with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was dissolved in methanol (10 mL) anddichloromethane (10 mL), and trifluoroacetic acid (4 mL) was addedthereto. The reaction mixture was stirred at room temperature overnight,and then stirred at 50° C. for two hours. The reaction mixture wasconcentrated under reduced pressure, and a saturated sodiumhydrogencarbonate aqueous solution was added thereto, followed byextraction with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was purified by column chromatography on silicagel (hexane:ethyl acetate=60:40→30:70) to obtain the title compound (447mg) having the following physical property values.

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.47, 6.93, 7.14, 7.58, 7.64, 8.24, 8.43,8.89.

Examples 5(1) to (35)

The corresponding amine instead of 1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride was used and subjected to the same procedureas in Example 5 to obtain the title compound having the followingphysical property values.

Example 5(1)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-(4-fluorobenzyl)urea

TLC: Rf 0.54 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.26, 6.89, 6.92, 7.10-7.19, 7.28-7.37, 7.63,8.15.

Example 5(2)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(5-fluoro-2-pyridinyl)methyl]urea

TLC: Rf 0.44 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 1.69, 4.37, 6.93, 7.05, 7.41, 7.64, 7.74, 8.36,8.50.

Example 5(3)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[6-(1-piperidinyl)-2-pyridinyl]methyl}urea

TLC: Rf 0.89 (ethyl acetate);

¹H-NMR (DMSO-d₆): δ 1.50-1.65, 1.69, 3.49-3.52, 4.19, 6.55, 6.65, 6.81,6.93, 7.46, 7.64, 8.31.

Example 5(4)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-(3,3-dimethyl-2-butanyl)urea

TLC: Rf 0.38 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 0.87, 0.95, 1.69, 3.44-3.54, 6.24, 6.91, 7.61, 7.83.

Example 5(5)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl]urea

TLC: Rf 0.19 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 0.91-1.05, 1.11, 1.50-1.54, 1.69, 1.75-1.87,2.98-2.96, 3.46-3.54, 3.58-3.63, 6.43, 6.92, 7.62, 7.94.

Example 5(6)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(4,4-difluoro-1-hydroxycyclohexyl) methyl]urea

TLC: Rf 0.25 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.43-1.66, 1.69, 1.76-2.15, 3.10, 4.70, 6.50, 6.92,7.62, 8.16.

Example 5(7)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(3-methyl-2-pyridinyl)methyl]urea

TLC: Rf 0.15 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 2.28, 4.40, 6.92, 7.10, 7.25, 7.61, 7.63,8.39, 8.53.

Example 5(8)1-[(5-chloro-2-thienyl)methyl]-3-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]urea

TLC: Rf 0.53 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.34, 6.82, 6.93-6.94, 7.01, 7.64, 8.21.

Example 5(9)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[3-(trifluoromethyl)-2-pyridinyl]methyl}urea

TLC: Rf 0.35 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.60, 6.93, 7.11, 7.57, 7.63, 8.19, 8.51,8.86.

Example 5(10) 1-(cyclohexylmethyl)-3-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]urea

TLC: Rf 0.59 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 0.80-1.78, 2.91, 6.38, 6.91, 7.61, 7.90.

Example 5(11)1-[(5-bromo-2-pyridinyl)methyl]-3-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]urea

TLC: Rf 0.50 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 1.69, 4.34, 6.93, 7.05, 7.34, 7.64, 8.06, 8.37,8.63.

Example 5(12)1-[(1-benzyl-1H-imidazole-2-yl)methyl]-3-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]urea

TLC: Rf 0.64 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.31, 5.23, 6.87, 6.92, 6.96, 7.16-7.19,7.28-7.37, 7.62, 8.24.

Example 5(13)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(5-fluoro-1H-indole-2-yl)methyl]urea

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.39, 6.29, 6.81-6.90, 6.93, 7.19-7.23,7.28-7.33, 7.64, 8.19, 11.02.

Example 5(14)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(2R)-tetrahydro-2-furanylmethyl]urea

TLC: Rf 0.43 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆): δ 1.47-1.62, 1.69, 1.72-1.95, 3.01-3.12, 3.13-3.28,3.59-3.66, 3.75-3.86, 6.45, 6.92, 7.62, 8.08.

Example 5(15)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(2S)-tetrahydro-2-furanylmethyl]urea

TLC: Rf 0.43 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆): δ 1.47-1.62, 1.69, 1.72-1.95, 3.01-3.12, 3.13-3.28,3.59-3.66, 3.75-3.86, 6.45, 6.92, 7.62, 8.08.

Example 5(16)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(5-phenyl-1,2-oxazole-3-yl)methyl]urea

TLC: Rf 0.37 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.37, 6.85, 6.93, 7.03, 7.43-7.58, 7.65, 7.82,8.30.

Example 5(17)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-furyl]methyl}urea

TLC: Rf 0.58 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.33, 6.44, 6.94, 6.97, 7.16, 7.64, 8.25.

Example 5(18)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]methyl}urea

TLC: Rf 0.65 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.54, 6.94, 7.14, 7.63, 8.43.

Example 5(19)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-(3,3,3-trifluoropropyl)urea

TLC: Rf 0.28 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 2.26-2.44, 3.27-3.29, 6.55, 6.93, 7.63, 8.22.

Example 5(20) 1-[(1R)-1-cyclopropylethyl]-3-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]urea

TLC: Rf 0.30 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 0.15-0.41, 0.82-0.89, 1.12, 1.69, 3.18-3.25, 6.30,6.91, 7.61, 7.85.

Example 5(21)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(2R)-3-methyl-2-butanyl]urea

TLC: Rf 0.30 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 0.84-0.88, 1.01, 1.61-1.70, 3.46-3.53, 6.24, 6.91,7.61, 7.82.

Example 5(22)1-[(3-cyclopropyl-1,2,4-oxadiazole-5-yl)methyl]-3-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]urea

TLC: Rf 0.17 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 0.82-0.87, 1.01-1.08, 1.69, 2.05-2.14, 4.47, 6.93,7.10, 7.63, 8.46.

Example 5(23)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-1,2-oxazole-3-yl]methyl}urea

TLC: Rf 0.45 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.42, 6.94, 7.08, 7.18, 7.64, 8.41.

Example 5(24)1-[(5-chloro-2-pyrimidinyl)methyl]-3-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]urea

TLC: Rf 0.60 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆): δ 1.69, 4.49, 6.92, 7.01, 7.62, 8.42, 8.92.

Example 5(25)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyrazinyl]methyl}urea

TLC: Rf 0.38 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.55, 6.94, 7.21, 7.64, 8.51, 8.78, 9.13.

Example 5(26)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-thienyl]methyl}urea

TLC: Rf 0.54 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.48, 6.94, 7.05, 7.14, 7.54, 7.64, 8.31.

Example 5(27)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[3-(2-methyl-2-propanyl)-1,2,4-oxadiazole-5-yl]methyl}urea

TLC: Rf 0.41 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.29, 1.69, 4.52, 6.93, 7.13, 7.63, 8.47.

Example 5(28)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(2-methyl-2-propanyl)-1,2,4-oxadiazole-3-yl]methyl}urea

TLC: Rf 0.36 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.37, 1.69, 4.37, 6.92, 6.99, 7.63, 8.29.

Example 5(29)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[4-(trifluoromethyl)benzyl]urea

LC retention time (min), LC condition 2: 0.96;

¹H-NMR (DMSO-d₆): δ 1.68, 4.36, 6.91, 7.00, 7.49-7.51, 7.63, 7.68-7.71,8.24.

Example 5(30) 1-(cyclopropylmethyl)-3-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]urea

TLC: Rf 0.53 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 0.16-0.21, 0.38-0.44, 0.89-0.97, 1.70, 2.97, 6.45,6.93, 7.63, 7.99.

Example 5(31)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(2,2-difluorocyclopropyl)methyl]urea

TLC: Rf 0.29 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.24-1.34, 1.51-1.62, 1.70, 1.86-1.99, 3.08-3.29,6.63, 6.94, 7.64, 8.13.

Example 5(32)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-(1,2-oxazole-3-ylmethyl)urea

TLC: Rf 0.34 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.35, 6.45, 6.94, 6.99, 7.65, 8.29, 8.83.

Example 5(33)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-(1,3-thiazole-2-ylmethyl)urea

TLC: Rf 0.12 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.71, 4.56, 6.95, 7.27, 7.61, 7.65, 7.72, 8.40.

Example 5(34)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(3,3-difluorocyclobutyl)methyl]urea

TLC: Rf 0.42 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 2.27-2.65, 3.19, 6.60, 6.93, 7.63, 8.07.

Example 5(35)1-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[4-(trifluoromethoxy)benzyl]urea

TLC: Rf 0.55 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 1.72, 4.42, 7.22-7.25, 7.43-7.46, 7.66.

Example 6 [2-(2-methyl-2-propanyl)-1,3-oxazole-5-yl]methanol

To a methanol solution (1.3 mL) of[2-(2-methyl-2-propanyl)-1,3-oxazole-5-yl] methyl acetate (52 mg)(Tetrahedron Letters, 2010, vol. 51, p. 2247-2250), potassium carbonate(54 mg) was added under ice-cooling. The reaction mixture was stirred atroom temperature for 30 minutes, and then water was added to themixture, followed by extraction with ethyl acetate. The organic layerwas washed sequentially with water and saturated brine, and dried overanhydrous sodium sulfate, followed by concentration under reducedpressure to obtain the title compound (40 mg) having the followingphysical property values.

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.39, 1.71, 4.65, 6.88.

Example 7 2-{[2-(2-methyl-2-propanyl)-1,3-oxazole-5-yl]methyl}-1H-isoindole-1,3(2H)-dione

Under argon atmosphere, triphenylphosphine (135 mg) and phthalimide (75mg) were added to a tetrahydrofuran solution (1 mL) of the compound (40mg) produced in Example 6. Diethyl azodicarboxylate (230 μL) was addedto the reaction mixture under ice-cooling, and the resulting mixture wasstirred at room temperature for one hour. The reaction mixture wasconcentrated. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=80/20→55/45) toobtain the title compound (93 mg) having the following physical propertyvalues.

TLC: Rf 0.64 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.34, 4.87, 6.93, 7.73-7.78, 7.86-7.90.

Example 8 1-[2-(2-methyl-2-propanyl)-1,3-oxazole-5-yl]methanamine

Under argon atmosphere, hydrazine 1-hydrate (129 mg) was added to anethanol solution (1.7 mL) of the compound (73 mg) produced in Example 7.The reaction mixture was stirred at 80° C. for 30 minutes, and thencooled to room temperature. To the reaction mixture, a mixed solvent ofethyl acetate and ethanol was added. The resulting mixture solution wasfiltered. The filtrate was concentrated under reduced pressure to obtainthe title compound (40 mg) having the following physical propertyvalues.

¹H-NMR (CDCl₃): δ 1.37, 3.85, 6.74.

Example 91-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[2-(2-methyl-2-propanyl)-1,3-oxazole-5-yl]methyl}urea

The compound produced in Example 8 instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride was usedand subjected to the same procedure as in Example 5 to obtain the titlecompound having the following physical property values.

TLC: Rf 0.40 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 1.29, 1.69, 4.28, 6.78, 6.84, 6.93, 7.64, 8.17.

Example 10 1-[2-(trifluoromethyl)-1,3-thiazole-5-yl]methanamine

(2-(trifluoromethyl)thiazole-5-yl)methanol (CAS registry number:131748-97-5) instead of the compound produced in Example 6 was used andsubjected to the same procedure as in Example 7→Example 8 to obtain thetitle compound having the following physical property values.

¹H-NMR (DMSO-d₆): δ 2.27, 4.00, 7.91.

Example 111-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea

The compound produced in Example 10 instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride was usedand subjected to the same procedure as in Example 5 to obtain the titlecompound having the following physical property values.

TLC: Rf 0.26 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.53, 6.94, 7.19, 7.65, 7.96, 8.40.

Example 12 1-[5-(2-methyl-2-propanyl)-1,2-oxazole-3-yl]methanamine

(5-tert-butyl-1,2-oxazole-3-yl)methanol (CAS registry number:202817-06-9) instead of the compound produced in Example 6 was used andsubjected to the same procedure as in Example 7→Example 8 to obtain thetitle compound having the following physical property values.

¹H-NMR (DMSO-d₆): δ 1.27, 3.63, 6.20.

Example 131-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(2-methyl-2-propanyl)-1,2-oxazole3-yl]methyl}urea

The compound produced in Example 12 instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride was usedand subjected to the same procedure as in Example 5 to obtain the titlecompound having the following physical property values.

TLC: Rf 0.53 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.27, 1.69, 4.26, 6.10, 6.91-6.99, 7.64, 8.27.

Example 14 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol

Under argon atmosphere, cerium chloride (51 g), which had been heatedand dried under reduced pressure, was suspended in tetrahydrofuran (316mL), stirred at room temperature for one hour, and the resulting mixturewas cooled to −70° C. Methyllithium (3.0 M diethyl ether solution, 185mL) was added dropwise, stirred at −70° C. for 30 minutes. Atetrahydrofuran solution (30 mL) of1-(4-bromophenyl)-2,2,2-trifluoroethanone (40 g) (CAS registry number:16184-89-7) was added to the resulting mixture. The resulting solutionwas stirred at room temperature for 1.5 hours. The reaction solution waspoured into a mixed solution of a saturated ammonium chloride aqueoussolution (500 mL) and ice water (500 mL), and 1 N hydrochloric acid wasadded to the resulting solution until the mixture became light yellow,followed by extraction with ethyl acetate. The organic layer was washedsequentially with water and saturated brine, and dried over anhydrousmagnesium sulfate, followed by concentration under reduced pressure toobtain the title compound (51 g) having the following physical propertyvalues.

TLC: Rf 0.59 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 1.77, 2.42, 7.44-7.47, 7.52-7.55.

Examples 15a and 15b(2R)-2-(4-bromophenyl)-1,1,1-trifluoro-2-propanyl[(1S)-1-(1-naphthyl)ethyl]carbamate(15a) and(2S)-2-(4-bromophenyl)-1,1,1-trifluoro-2-propanyl[(1S)-1-(1-naphthyl)ethyl]carbamate(15b)

To a dichloromethane solution (237 mL) of the compound (43 g) producedin Example 14, dimethyl amino pyridine (23.2 g) and 4-nitrophenylchloroformate (35.1 g) were added under ice-cooling, and the resultingmixture was stirred at room temperature for one hour. The reactionsolution was cooled with ice, (1S)-1-(1-naphthyl)ethyl amine (33.2 mL)(CAS registry number: 10420-89-0) was added thereto. The resultingsolution was stirred at room temperature for one hour. To the reactionmixture, tert-butyl methyl ether (500 mL) was added, and the precipitatewas separated by filtration. The precipitate washed with hexane/ethylacetate (1/1). The filtrate and the washing solution were combinedtogether, and concentrated under reduced pressure until the amountbecame the half. The resulting product was washed with 1 N sodiumhydroxide aqueous solution (150 mL×four times), 1N hydrochloric acid(200 mL), water (150 mL), and saturated brine, sequentially, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was purified by column chromatography on silicagel (hexane:ethyl acetate=90:10→80:20) to obtain a diastereomer mixtureof the title compound (70 g). The diastereomer mixture was separated andpurified by column chromatography on silica gel (hexane:tert-butylmethyl ether=80:20) to obtain the title compounds 15a (28 g) and 15b (33g) having the following physical property values.

15a

TLC: Rf 0.39 (hexane:diisopropyl ether=2:1);

¹H-NMR (CDCl₃): δ 1.63, 2.07, 5.35, 5.50-5.60, 7.32-7.35, 7.42-7.58,7.78-7.90, 8.02-8.07.

15b

TLC: Rf 0.58 (hexane:diisopropyl ether=2:1);

¹H-NMR (CDCl₃): δ 1.69, 2.17, 5.25, 5.49-5.58, 7.22-7.25, 7.43-7.58,7.80-7.95.

Example 16 (2R)-2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol

To a 1,4-dioxane solution (475 mL) of the compound (44 g) produced inExample 15a, an aqueous solution (237 mL) of lithium hydroxide 1 hydrate(40 g) was added. The resulting solution was stirred at 55° C. for onehour. The reaction mixture was cooled to 10° C., and then 2Nhydrochloric acid (520 mL) was added to the mixture so that pH was 2,followed by extraction with ethyl acetate. The organic layer was washedsequentially with a sodium hydrogencarbonate aqueous solution, water, anammonium chloride aqueous solution, and saturated brine, then dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=90:10→80:20) to obtain the titlecompound (27 g) having the following physical property values.

TLC: Rf 0.59 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 1.78, 2.42, 7.43-7.56.

Example 17 2-methyl-2-propanyl{4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}carbamate

A mixture of the compound (27 g) produced in Example 16, tert-butylcarbamate (15 g), palladium acetate (II) (2.2 g),4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (8.6 g), cesiumcarbonate (49 g), 1,4-dioxane (200 mL) was stirred under argonatmosphere at 100° C. for two hours. The reaction mixture was cooled toroom temperature, and then, water (250 mL) and ethyl acetate (250 mL)were added thereto. The resulting mixture was filtered through a Celite(product name). Water (250 mL) was added to the filtrate to separate twolayers. Thereafter, the water layer was extracted with ethyl acetate.The extract layer was combined with the organic layer. It was washedsequentially with an ammonium chloride aqueous solution and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=90:10→50:50) toobtain the title compound (26g) having the following physical propertyvalues.

TLC: Rf 0.31 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 1.52, 1.77, 2.56, 6.57, 7.37-7.40, 7.48-7.51.

Example 18 (2R)-2-(4-aminophenyl)-1,1,1-trifluoro-2-propanol

To a dichloromethane solution (170 mL) of the compound (26 g) producedin Example 17, trifluoroacetic acid (85 mL) was added. The resultingmixture was stirred at room temperature for 1.5 hours. To the reactionmixture, toluene was added, followed by concentration under reducedpressure. To the resulting residue, a saturated sodium hydrogencarbonateaqueous solution (300 mL) was added, followed by extraction with ethylacetate. The organic layer was washed sequentially with an ammoniumchloride aqueous solution and saturated brine, then dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was dissolved in tert-butyl methyl ether-hexane (1:1,30 mL) at 60° C. The resulting solution was cooled to 5° C., andprecipitate solids were filtered. The filtrate was concentrated toobtain the title compound (9.8 g) having the following physical propertyvalues.

TLC: Rf 0.34 (hexane:ethyl acetate=3:2);

¹H-NMR (CDCl₃): δ 1.74, 2.38, 3.77, 6.67-6.70, 7.33-7.36.

Example 19 (2R)-2-(4-aminophenyl)-1,1,1-trifluoro-2-propanolHydrochloride

A tert-butyl methyl ether solution (96 mL) of the compound (9.8 g)produced in Example 18 was cooled in ice bath, and 4 N hydrogenchloride/1,4-dioxane solution (15 mL) was added thereto. The resultingmixture was stirred. The generated precipitate was collected byfiltration and washed with tert-butyl methyl ether. To the resultingsolid, acetonitrile (200 mL) was added, followed by stirring at 80° C.After dissolving, the resulting solution was cooled to room temperatureand was stirred overnight. The precipitated crystal was collected byfiltration, and washed sequentially with acetonitrile and ethyl acetate,and then dried to obtain the title compound (7.8 g) having the followingphysical property values.

TLC: Rf 0.34 (hexane:ethyl acetate=3:2);

¹H-NMR (DMSO-d₆): δ 1.64, 3.57, 6.61, 7.19-7.22, 7.58-7.61.

Example 204-{(2R)-1,1,1-trifluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

The compound produced in Example 19 (7.8 g) was dissolved in methanol(10 mL) and ethyl acetate (50 mL), and a saturated sodiumhydrogencarbonate aqueous solution (150 mL) was added in severalportions while stirring. Then, the reaction mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. To the resulting residue, a tetrahydrofuran solution (130 mL)was added. The resulting mixture was cooled in ice water bath, andimidazole (11 g) and chlorotrimethylsilane (20 mL) were added thereto,followed by stirring at 30° C. for one hour. The reaction mixture waspoured into water (300 mL), the water layer was separated. A saturatedsodium hydrogencarbonate aqueous solution was added thereto so as tomake pH at 7 or more, followed by extraction with ethyl acetate. Theorganic layer was washed sequentially with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure to obtain the title compound (9.4 g) having the followingphysical property values.

TLC: Rf 0.54 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 0.12, 1.77, 3.69, 6.64-6.67, 7.29-7.32.

Example 212,6-dichloro-4-{(2R)-1,1,1-trifluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

To an N,N-dimethylformamide solution (100 mL) of the compound (9.4 g)produced in Example 20, N-chlorosuccinimide (9.1 g) was added. Theresulting mixture was stirred at room temperature for 15 hours, and wasfurther stirred at 40° C. for two hours. The reaction mixture was pouredinto water (300 mL), followed by extraction with hexane-ethyl acetate(1:1, 100 mL×three times). The organic layer was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=90:10→50:50) toobtain the title compound (9.0 g) having the following physical propertyvalues.

TLC: Rf 0.55 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 0.15, 1.75, 4.51, 7.33.

Example 221-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-[(5-methyl-1,2-oxazole3-yl) methyl]urea

To a tetrahydrofuran solution (5 mL) of the compound produced in Example21 (300 mg), N,N-diisopropyl ethyl amine (160 μL) and triphosgene (283mg) were added. The reaction mixture was stirred at room temperature for30 minutes, and concentrated under reduced pressure. The resultingresidue was dissolved in tetrahydrofuran (5 mL), and1-(5-methyl-1,2-oxazole-3-yl)methanamine hydrochloride (154 mg) (CASregistry number: 1050590-34-5) and triethylamine (290 μL) were added tothe solution. The resulting solution was stirred at 50° C. for one hour.Water was added to the reaction mixture, followed by extraction withethyl acetate. The organic layer was washed sequentially with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. Methanol (4 mL) and trifluoroaceticacid (1.8 mL) were added to the resulting residue, followed by stirringat room temperature for one hour. The reaction mixture was concentratedunder reduced pressure, and a saturated sodium hydrogencarbonate aqueoussolution was added thereto, followed by extraction with ethyl acetate.The organic layer was washed sequentially with water and saturatedbrine, dried over anhydrous sodium sulfate, and then concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=90:10→70/30→50:50) toobtain the title compound (310 mg) having the following physicalproperty values.

TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 2.37, 4.26, 6.10, 6.90-6.97, 7.64, 8.24.

Examples 22(1) to (17)

Amine produced in Example 10 or the corresponding amine instead of1-(5-methyl-1,2-oxazole-3-yl)methanamine hydrochloride was used andsubjected to the same procedure as in Example 22 to obtain the titlecompound having the following physical property values.

Example 22(1)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

TLC: Rf 0.16 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.75, 2.77, 4.65, 5.76, 6.60, 7.49, 7.61, 7.91-7.95,8.78.

Example 22(2)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea

TLC: Rf 0.34 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.61, 6.92, 7.08, 7.62, 8.46, 9.25.

Example 22(3)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.40, 6.93, 7.08, 7.64, 7.87-7.99, 8.35, 8.68.

Example 22(4)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[2-(trifluoromethyl)-5-pyrimidinyl]methyl}urea

TLC: Rf 0.23 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.42, 6.94, 7.12, 7.64, 8.46, 8.95.

Example 22(5)1-[(5-chloro-2-pyridinyl)methyl]-3-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea

TLC: Rf 0.20 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.36, 6.93, 7.06, 7.39, 7.64, 7.94, 8.37,8.55.

Example 22(6)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[6-(2,2,2-trifluoroethoxy)-3-pyridinyl]methyl}urea

TLC: Rf 0.38 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.25, 4.93-5.02, 6.93-6.98, 7.64, 7.74, 8.11,8.19.

Example 22(7)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-[4-(trifluoromethyl)benzyl]urea

TLC: Rf 0.60 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.38, 6.94, 7.02, 7.50-7.53, 7.65, 7.69-7.72,8.26.

Example 22(8)1-benzyl-3-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea

LC retention time (min), LC condition 3: 0.90;

¹H-NMR (DMSO-d₆): δ 1.70, 4.29, 6.89, 6.95, 7.20-7.35, 7.64, 8.14.

Example 22(9)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-(4-methoxybenzyl)urea

LC retention time (min), LC condition 3: 0.90;

¹H-NMR (DMSO-d₆): δ 1.69, 3.72, 4.21, 6.79, 6.87-6.92, 7.20-7.23, 7.63,8.07.

Example 22(10)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-(4-methylbenzyl)urea

LC retention time (min), LC condition 3: 0.95;

¹H-NMR (DMSO-d₆): δ 1.70, 2.27, 4.24, 6.82, 6.94, 7.14-7.20, 7.64, 8.10.

Example 22(11)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-[4-(2-methyl-2-propanyl)benzyl]urea

LC retention time (min), LC condition 3: 1.05;

¹H-NMR (DMSO-d₆): δ 1.27, 1.70, 4.25, 6.84, 6.92, 7.21-7.24, 7.34-7.36,7.64, 8.09.

Example 22(12)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-(4-phenoxybenzyl)urea

LC retention time (min), LC condition 3: 1.03;

¹H-NMR (DMSO-d₆): δ 1.70, 4.28, 6.87-6.91, 6.96-7.00, 7.09-7.15,7.31-7.41, 7.64, 8.14.

Example 22(13)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-[4-(difluoromethoxy)benzyl]urea

LC retention time (min), LC condition 3: 0.94;

¹H-NMR (DMSO-d₆): δ 1.70, 4.28, 6.88-6.94, 7.13-7.16, 7.20, 7.33-7.36,7.64, 8.16.

Example 22(14)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-[4-(4-morpholinyl)benzyl]urea

LC retention time (min), LC condition 3: 0.73;

¹H-NMR (DMSO-d₆): δ 1.70, 3.07-3.11, 3.72-3.75, 4.19, 6.77, 6.92-6.95,7.17-7.20, 7.64, 8.07.

Example 22(15)1-(4-cyanobenzyl)-3-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea

LC retention time (min), LC condition 3: 0.87;

¹H-NMR (DMSO-d₆): δ 1.70, 4.37, 6.93, 7.02, 7.47-7.50, 7.65, 7.80-7.82,8.28.

Example 22(16)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-[4-(4-fluorophenoxyl)benzyl]urea

LC retention time (min), LC condition 3: 1.03;

¹H-NMR (DMSO-d₆): δ 1.70, 4.27, 6.86-7.05, 7.19-7.23, 7.30-7.33, 7.64,8.13.

Example 22(17)1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.71, 4.55, 6.95, 7.20, 7.66, 7.98, 8.41.

Example 231-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea

To a tetrahydrofuran solution (6 mL) of the compound produced in Example21 (300 mg), N,N-diisopropyl ethyl amine (165 μL) and triphosgene (283mg) were added. The reaction mixture was stirred at room temperature forone hour, and then concentrated under reduced pressure. The resultingresidue was dissolved in tetrahydrofuran (6 mL),1-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methanamine hydrochloride(264 mg) (CAS registry number: 944905-93-5) and N,N-diisopropyl ethylamine (750 μL) were added. The reaction mixture was stirred at 45° C.for 17 hours. Then, tetrabutyl ammonium fluoride (1 M tetrahydrofuransolution, 1 mL) was added, and the mixture was stirred at roomtemperature for one hour. A saturated ammonium chloride aqueous solutionwas added to the reaction mixture, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was purified by column chromatography on silicagel (hexane:ethyl acetate=60:40) to obtain the title compound (380 mg)having the following physical property values.

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.68, 4.68, 6.93, 7.24, 7.63, 8.61.

Example 242,6-dichloro-4-{(2S)-1,1,1-trifluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

The compound produced in Example 15b instead of the compound produced inExample 15a was used and subjected to the same procedure as in Example16→Example 17→Example 18→Example 19→Example 20→Example 21 to obtain thetitle compound having the following physical property values.

TLC: Rf 0.56 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 0.15, 1.75, 4.51, 7.33.

Example 251-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-[(5-methyl-1,2-oxazole-3-yl)methyl]urea

The compound produced in Example 24 instead of the compound produced inExample 21 was used and subjected to the same procedure as in Example 22to obtain the title compound having the following physical propertyvalues.

TLC: Rf 0.30 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 2.37, 4.25, 6.10, 6.91-7.00, 7.64, 8.24.

Examples 25(1) to (8)

The compound produced in Example 24 instead of the compound produced inExample 21, and amine produced in Example 10 or the corresponding amineinstead of 1-(5-methyl-1,2-oxazole-3-yl)methanamine hydrochloride wereused and subjected to the same procedure as in Example 22 to obtain thetitle compound having the following physical property values.

Example 25(1)1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea

TLC: Rf 0.34 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.60, 6.92, 7.08, 7.62, 8.46, 9.25.

Example 25(2)1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea

TLC: Rf 0.29 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.40, 6.93, 7.08, 7.64, 7.89, 7.97, 8.35,8.67.

Example 25(3)1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[2-(trifluoromethyl)-5-pyrimidinyl]methyl}urea

TLC: Rf 0.21 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.41, 6.93, 7.12, 7.65, 8.46, 8.95.

Example 25(4)1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

TLC: Rf 0.16 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.76, 2.67, 4.65, 5.73, 6.60, 7.49, 7.61, 7.91-7.95,8.79.

Example 25(5)1-[(5-chloro-2-pyridinyl)methyl]-3-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea

TLC: Rf 0.24 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.69, 4.36, 6.93, 7.06, 7.38, 7.64, 7.94, 8.37,8.55.

Example 25(6)1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[6-(2,2,2-trifluoroethoxy)-3-pyridinyl]methyl}urea

TLC: Rf 0.37 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.25, 4.93-5.02, 6.93-6.98, 7.64, 7.74, 8.11,8.19.

Example 25(7)1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-[4-(trifluoromethyl)benzyl]urea

TLC: Rf 0.60 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.70, 4.38, 6.93, 7.02, 7.50-7.53, 7.65, 7.69-7.72,8.25.

Example 25(8)1-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.71, 4.55, 6.95, 7.19, 7.66, 7.98, 8.40.

Example 261-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea

The compound produced in Example 24 instead of the compound produced inExample 21 was used and subjected to the same procedure as in Example 23to obtain the title compound having the following physical propertyvalues.

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.68, 4.68, 6.92, 7.24, 7.63, 8.60.

Examples 27a and 27b (1R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl[(1S)-1-(1-naphthyl)ethyl]carbamate (27a) and(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl[(1S)-1-(1-naphthyl)ethyl]carbamate(27b)

To a dichloromethane solution (80 mL) of1-(4-bromophenyl)-2,2,2-trifluoroethanol (4.0 g) (CAS registry number:76911-73-4), 4-dimethyl amino pyridine (2.3 g) and 4-nitrophenylchloroformate (3.3 mL) were added under ice-cooling. The resultingmixture was stirred at room temperature for one hour. The reactionsolution was cooled again in ice, (1S)-1-(1-naphthyl)ethanamine (4 mL)(CAS registry number: 10420-89-0) was added thereto, followed bystirring at at room temperature for 30 minutes. The reaction solutionwas filtered, and the filtrate was washed sequentially with 1 N sodiumhydroxide aqueous solution twice, with 1 N hydrochloric acid once, andwith saturated brine once. The organic layer was dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by column chromatography on silica gel(hexane:tert-butyl methyl ether=90:10) to obtain the title compounds 27a(1.91 g) and 27b (2.44 g) having the following physical property values.

27a

TLC: Rf 0.57 (hexane:tert-butyl methyl ether=3:1);

¹H-NMR (CDCl₃): δ 1.65, 5.30, 5.64, 6.04, 7.34, 7.47-7.57, 7.82, 7.89,8.07.

27b

TLC: Rf 0.69 (hexane:tert-butyl methyl ether=3:1);

¹H-NMR (CDCl₃): δ 1.72, 5.29, 5.60, 6.03, 7.28, 7.41-7.51, 7.80, 7.86,7.94.

Example 28 (1R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol

To a mix solution of 1,4-dioxane (40 mL) and water (20 mL) of thecompound produced in Example 27a (2.37 g), lithium hydroxide 1 hydrate(2.20 g) was added, and the resulting mixture was stirred at 50° C. forone hour. To the reaction mixture, 2 N hydrochloric acid (40 mL) wasadded in an ice bath, followed by extraction with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=90:10) toobtain the title compound (1.34 g) having the following physicalproperty values.

TLC: Rf 0.65 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 2.57, 4.97-5.05, 7.35-7.38, 7.54-7.57.

Example 292-methyl-2-propanyl{4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}carbamate

To a 1,4-dioxane solution (30 mL) of the compound produced in Example 28(1.34 g), tert-butyl carbamate (800 mg), palladium acetate (II) (118mg), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (456 mg), andcesium carbonate (2.57 g) were added. The resulting mixture was heatedand refluxed for three hours. The reaction mixture was filtered througha Celite (product name), and the filtrate was concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=80:20) to obtain the title compound(1.32 g) having the following physical property values.

TLC: Rf 0.48 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 1.52, 2.58, 4.98, 6.56, 7.40.

Example 30 (1R)-1-(4-amino-3,5-dichlorophenyl)-2,2,2-trifluoroethanol

To a dichloromethane solution (20 mL) of the compound produced inExample 29 (1.32 g), trifluoroacetic acid (10 mL) was added in an icebath. The resulting mixture was stirred at room temperature for onehour. Toluene (10 mL) was added to the reaction mixture, followed byconcentration under reduced pressure. A saturated sodiumhydrogencarbonate aqueous solution was added to the resulting residue,followed by extraction with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate, and then concentrated under reducedpressure. The resulting residue was dissolved in N,N-dimethylformamide(10 mL), and N-chlorosuccinimide (684 mg) to the resulting solution. Thereaction mixture was stirred at 40° C. for 18 hours. Water was added tothe reaction mixture, followed by extraction with a mixed solvent ofethyl acetate and hexane. The organic layer was dried over anhydrousmagnesium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by column chromatography on silica gel(hexane:ethyl acetate=85:15) to obtain the title compound (310 mg)having the following physical property values.

TLC: Rf 0.50 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 4.58, 4.83-4.91, 7.31.

Example 312,6-dichloro-4-{(1R)-2,2,2-trifluoro-1-[(trimethylsilyl)oxy]ethyl}aniline

To a tetrahydrofuran solution (10 mL) of the compound produced inExample 30 (310 mg), chlorotrimethylsilane (583 μL) and imidazole (405mg) were added. The resulting mixture was stirred at room temperaturefor three hours. A saturated ammonium chloride aqueous solution wasadded to the reaction mixture, followed by extraction with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (hexane:ethylacetate=95:5) to obtain the title compound (396 mg) having the followingphysical property values.

TLC: Rf 0.75 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 0.13, 4.56, 4.75, 7.26.

Example 321-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

To a tetrahydrofuran solution (4 mL) of the compound produced in Example31 (80 mg), N,N-diisopropyl amine (49 μL) and triphosgene (78 mg) wereadded. The reaction mixture was stirred at room temperature for twohours, and then concentrated under reduced pressure. The resultingresidue was dissolved in tetrahydrofuran (4 mL), and1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride (76 mg) andN,N-diisopropyl ethyl amine (83 μL) were added thereto. The reactionmixture was stirred at 50° C. for two hours, and then a saturated sodiumhydrogencarbonate aqueous solution was added thereto, followed byextraction with ethyl acetate. The organic layer was washed sequentiallywith water and saturated brine, and then dried over anhydrous sodiumsulfate, followed by concentration under reduced pressure. The resultingresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=100:0→90/10→50/50) to obtain the title compound(67 mg) having the following physical property values.

TLC: Rf 0.21 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 4.58, 5.07, 7.57, 7.64, 8.11, 8.80.

Examples 32(1) to (7)

The corresponding amine instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride was usedand subjected to the same procedure as in Example 32 to obtain the titlecompound having the following physical property values.

Example 32(1)1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea

TLC: Rf 0.38 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 4.68, 5.27, 7.13, 7.25, 7.57, 8.62.

Example 32(2)1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-[(5-methyl-1,2-oxazole-3-yl)methyl]urea

TLC: Rf 0.23 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.36, 4.24, 5.27, 6.09, 6.95, 7.17, 7.57, 8.27.

Example 32(3)1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-5-pyrimidinyl]methyl}urea

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 4.41, 5.27, 7.10-7.14, 7.58, 8.47, 8.94.

Example 32(4)1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea

TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 4.72, 5.06, 7.55, 9.08.

Example 32(5)1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea

TLC: Rf 0.29 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 4.51, 5.08, 7.57, 7.78, 8.00, 8.69.

Example 32(6)1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[6-(2,2,2-trifluoroethoxy)-3-pyridinyl]methyl}urea

TLC: Rf 0.36 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 4.24, 4.92-5.01, 5.27, 6.92-6.97, 7.11, 7.58, 7.73,8.10, 8.19.

Example 32(7)1-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-[4-(trifluoromethyl)benzyl]urea

TLC: Rf 0.55 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 4.38, 5.24-5.33, 7.02, 7.13, 7.50-7.53, 7.59,7.69-7.72, 8.27.

Example 331-{2,6-dichloro-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea

The compound produced in Example 10 instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride was usedand subjected to the same procedure as in Example 32 to obtain the titlecompound having the following physical property values.

TLC: Rf 0.33 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 4.53, 5.27, 7.12, 7.18, 7.58, 7.95, 8.40.

Example 342,6-dichloro-4-{(1S)-2,2,2-trifluoro-1-[(trimethylsilyl)oxy]ethyl}aniline

The compound produced in Example 27b instead of the compound produced inExample 27a was used and subjected to the same procedure as in Example28→Example 29→Example 30→Example 31 to obtain the title compound havingthe following physical property values.

TLC: Rf 0.75 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 0.13, 4.56, 4.75, 7.26.

Example 351-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

The compound produced in Example 34 instead of the compound produced inExample 31 was used and subjected to the same procedure as in Example 32to obtain the title compound having the following physical propertyvalues.

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 4.58, 5.08, 7.57, 7.64, 8.11, 8.80.

Examples 35(1) to (7)

The compound produced in Example 34 instead of the compound produced inExample 31, and the corresponding amine instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride were usedand subjected to the same procedure as in Example 32 to obtain the titlecompound having the following physical property values.

Example 35(1)1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}urea

TLC: Rf 0.38 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 4.68, 5.28, 7.14, 7.26, 7.58, 8.63.

Example 35(2)1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-[(5-methyl-1,2-oxazole-3-yl)methyl]urea

TLC: Rf 0.23 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.36, 4.24, 5.27, 6.09, 6.95, 7.17, 7.57, 8.27.

Example 35(3)1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-5-pyrimidinyl]methyl}urea

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 4.41, 5.27, 7.10-7.14, 7.58, 8.47, 8.94.

Example 35(4)1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea

TLC: Rf 0.48 (hexane:ethyl acetate=3:2);

¹H-NMR (CD₃OD): δ 4.72, 5.07, 7.56, 9.09.

Example 35(5)1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea

TLC: Rf 0.29 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 4.51, 5.08, 7.57, 7.79, 8.00, 8.69.

Example 35(6)1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[6-(2,2,2-trifluoroethoxy)-3-pyridinyl]methyl}urea

TLC: Rf 0.38 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 4.24, 4.92-5.01, 5.27, 6.90-6.97, 7.11, 7.58, 7.73,8.10, 8.20.

Example 35(7)1-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-[4-(trifluoromethyl)benzyl]urea

TLC: Rf 0.55 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 4.38, 5.24-5.31, 7.02, 7.13, 7.50-7.53, 7.59,7.69-7.72, 8.27.

Example 361-{2,6-dichloro-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea

The compound produced in Example 10 instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride was usedand subjected to the same procedure as in Example 32 to obtain the titlecompound having the following physical property values.

TLC: Rf 0.33 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 4.53, 5.27, 7.12, 7.18, 7.58, 7.96, 8.39.

Example 37 4-acetyl-3-fluorophenyl Trifluoromethane Sulfonate

1-(2-fluoro-4-hydroxyphenyl)ethanone (2.05 g) (CAS registry number:68301-59-7) was suspended in dichloromethane (20 mL), and triethylamine(2.04 mL) and trifluoromethane sulfonic acid anhydride (2.46 mL) wereadded thereto under ice-cooling. The reaction mixture was stirred atroom temperature for 30 minutes, followed by concentration under reducedpressure. The resulting residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=100:0→90/10→70/30) to obtain the titlecompound (3.90 g) having the following physical property values.

TLC: Rf 0.69 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 2.67, 7.13-7.21, 8.02.

Example 38 3-fluoro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenylTrifluoromethane Sulfonate

To a tetrahydrofuran solution (13.6 mL) of the compound produced inExample 37 (3.90 g), (trifluoromethyl)trimethylsilane (3.88 g) andtetrabutyl ammonium fluoride (1 M tetrahydrofuran solution, 40 μL) wereadded. The reaction mixture was stirred at room temperature for 14hours, and then (trifluoromethyl)trimethylsilane (2.9 g) was added,followed by stirring at room temperature for six hours. The reactionmixture was cooled in ice, and then tetrabutyl ammonium fluoride (1 Mtetrahydrofuran solution, 7 mL) was added to the reaction mixture,followed by stirring at room temperature for five minutes. To thereaction mixture, 1N hydrochloric acid was added, followed by extractionwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=90/10→60/40) to obtain the title compound (2.06 g)having the following physical property values.

TLC: Rf 0.26 (hexane:ethyl acetate=6:1);

¹H-NMR (CDCl₃): δ 1.90-1.92, 2.81, 7.07-7.11, 7.15-7.18, 7.82.

Example 39 2-methyl-2-propanyl[3-fluoro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]carbamate

To a 1,4-dioxane solution (22.4 mL) of the compound produced in Example38 (1.49 g), tert-butyl carbamate (735 mg), palladium acetate (II) (93mg), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (363 mg), andcesium carbonate (2.04 g) were added. Then, the resulting mixture wasstirred under argon atmosphere at 110° C. for 1.5 hours. Insolublematter in the reaction mixture was separated by filtration. Filtrate wasconcentrated. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=95/5→75/25) to obtainthe title compound (1.12 g) having the following physical propertyvalues.

TLC: Rf 0.40 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 1.52, 1.83, 3.10, 6.57, 6.97-7.00, 7.38-7.47.

Example 40 2-(4-amino-2-fluorophenyl)-1,1,1-trifluoro-2-propanol

To a dichloromethane solution (22 mL) of the compound produced inExample 39 (1.12 g), and trifluoroacetic acid (5 mL) was added theretounder ice-cooling. The resulting mixture was stirred at room temperaturefor 14 hours, followed by concentration under reduced pressure. Theresulting residue was purified by column chromatography on silica gel(hexane:ethyl acetate=80/20→60/40) to obtain the title compound (540 mg)having the following physical property values.

TLC: Rf 0.25 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 1.79, 3.14, 3.86, 6.35-6.41, 6.44-6.48, 7.23-7.29.

Example 412-(4-amino-3,5-dichloro-2-fluorophenyl)-1,1,1-trifluoro-2-propanol

To an N,N-dimethylformamide solution (5 mL) of the compound produced inExample 40 (290 mg), N-chlorosuccinimide (347 mg) was added, and theresulting mixture was stirred at 80° C. for 17 hours. Water was added tothe reaction mixture, followed by extraction with a mixed solvent ofethyl acetate and hexane (1:1). The organic layer was dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was purified by column chromatography on silicagel (hexane:ethyl acetate=90/10) to obtain the title compound (219 mg)having the following physical property values.

TLC: Rf 0.49 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.84, 2.82, 4.67, 7.46.

Example 422,6-dichloro-3-fluoro-4-{1,1,1-trifluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

To a tetrahydrofuran solution (5 mL) of the compound produced in Example41 (250 mg), chlorotrimethylsilane (419 μL) and imidazole (291 mg) wereadded, and the resulting mixture was stirred at 55° C. for three hours.A saturated ammonium chloride aqueous solution was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=95/5) to obtain thetitle compound (310 mg) having the following physical property values.

TLC: Rf 0.65 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 0.19, 1.89, 4.63, 7.45.

Example 431-[2,6-dichloro-3-fluoro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

The compound produced in Example 42 instead of the compound produced inExample 4 was used and subjected to the same procedure as in Example 5to obtain the title compound having the following physical propertyvalues.

TLC: Rf 0.30 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 1.84, 4.59, 7.64, 7.85, 8.12, 8.81.

Examples 43(1) to (3)

The compound produced in Example 42 instead of the compound produced inExample 4, and the corresponding amine instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride were usedand subjected to the same procedure as in Example 5 to obtain the titlecompound having the following physical property values.

Example 43(1)1-[2,6-dichloro-3-fluoro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea

TLC: Rf 0.29 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 1.83, 4.72, 7.83, 9.10.

Example 43(2)1-[(5-chloro-2-pyridinyl)methyl]-3-[2,6-dichloro-3-fluoro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]urea

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

¹H-NMR (CD₃OD): δ 1.84, 4.49, 7.45, 7.82-7.86, 8.49.

Example 43(3)1-[2,6-dichloro-3-fluoro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]methyl}urea

TLC: Rf 0.64 (hexane:ethyl acetate=1:2);

¹H-NMR (CD₃OD): δ 1.83, 4.63, 7.84.

Example 44 4-acetyl-2-fluorophenyl Trifluoromethane Sulfonate

To a dichloromethane solution (20 mL) of1-(3-fluoro-4-hydroxyphenyl)ethanone (1.0 g) (CAS registry number:403-14-5), triethylamine (995 μL) and trifluoromethane sulfonic acidanhydride (1.2 mL) were added under ice-cooling. The resulting mixturewas stirred at room temperature for one hour. A saturated sodiumhydrogencarbonate aqueous solution was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=90/10) to obtain the title compound(1.8 g) having the following physical property values.

TLC: Rf 0.57 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 2.63, 7.46, 7.80-7.88.

Example 45 2-fluoro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenylTrifluoromethane Sulfonate

To a tetrahydrofuran solution (54 mL) of the compound produced inExample 44 (1.8 g) and (trifluoromethyl)trimethylsilane (2.8 mL),tetrabutyl ammonium fluoride (1 M tetrahydrofuran solution, 310 μL) wasadded in an ice bath, and the resulting mixture was stirred at roomtemperature for two hours. Tetrabutyl ammonium fluoride (1 Mtetrahydrofuran solution, 7.5 mL) was added to the reaction mixtureunder ice-cooling, followed by stirring for 10 minutes. A saturatedsodium hydrogencarbonate aqueous solution was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=90/10) to obtain thetitle compound (855 mg) having the following physical property values.

¹H-NMR (CDCl₃): δ 1.79, 2.52, 7.35-7.45, 7.56.

Example 46 2-methyl-2-propanyl[2-fluoro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]carbamate

To a 1,4-dioxane solution (12 mL) of the compound produced in Example 45(855 mg), tert-butyl carbamate (421 mg), palladium acetate (II) (54 mg),4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (208 mg), and cesiumcarbonate (1.17 g) were added and reacted under irradiation withmicrowave (Initiator60, manufactured by Biotage) at 110° C. for onehour. The reaction mixture was filtered through Celite (product name),and the filtrate was concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=80/20) to obtain the title compound (160 mg)having the following physical property values.

TLC: Rf 0.85 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 1.53, 1.75, 2.36, 6.74, 7.27-7.39, 8.11.

Example 47 2-(4-amino-3-fluorophenyl)-1,1,1-trifluoro-2-propanol

To a dichloromethane solution (4 mL) of the compound produced in Example46 (160 mg), trifluoroacetic acid (2 mL) was added in an ice bath. Theresulting mixture was stirred at room temperature for one hour. Toluene(2 mL) was added to the reaction mixture, followed by concentrationunder reduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=70/30) to obtain thetitle compound (53 mg) having the following physical property values.

TLC: Rf 0.65 (hexane:ethyl acetate=2:1);

¹H-NMR (CD₃OD): δ 1.67, 6.95, 7.20, 7.28.

Example 482-chloro-6-fluoro-4-{1,1,1-trifluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

To an N,N-dimethylformamide solution (2 mL) of the compound produced inExample 47 (53 mg), N-chlorosuccinimide (32 mg) was added, and theresulting mixture was stirred at room temperature for 18 hours. Waterwas added to the reaction mixture, followed by extraction with a mixedsolvent of ethyl acetate and hexane. The organic layer was dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was dissolved in tetrahydrofuran (2 mL), andchlorotrimethylsilane (116 μL) and imidazole (80 mg) were added to thesolution, and the solution was stirred at room temperature for twohours. A saturated ammonium chloride aqueous solution was added to thereaction mixture, followed by extraction with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, and then concentratedunder reduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=95/5) to obtain thetitle compound (53 mg) having the following physical property values.

TLC: Rf 0.84 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 0.15, 1.75, 4.13, 7.13, 7.20.

Example 491-[2-chloro-6-fluoro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

The compound produced in Example 48 instead of the compound produced inExample 4 was used and subjected to the same procedure as in Example 5to obtain the title compound having the following physical propertyvalues.

TLC: Rf 0.18 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 1.70, 4.59, 7.38, 7.53, 7.62, 8.12, 8.82.

Example 502-cyclohexyl-N-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]acetamide

To a toluene solution (2 mL) of the compound produced in Example 4 (50mg), cyclohexylacetyl chloride (27 mg) was added, followed by stirringunder irradiation with microwave (Initiator60, manufactured by Biotage)at 100° C. for one hour. Tetrabutyl ammonium fluoride (1 Mtetrahydrofuran solution, 288 μL) was added to the reaction mixture, andthe resulting mixture was stirred at room temperature for 20 hours. Asaturated sodium hydrogencarbonate aqueous solution was added to thereaction mixture, followed by extraction with ethyl acetate. The organiclayer was concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (hexane:ethylacetate=60/40) to obtain the title compound (8 mg) having the followingphysical property values.

TLC: Rf 0.50 (hexane:ethyl acetate=3:1);

¹H-NMR (CD₃OD): δ 1.02-1.40, 1.65-1.91, 2.31, 7.67.

Examples 50(1) to (7)

The corresponding acid chloride instead of cyclohexylacetyl chloride wasused and subjected to the same procedure as in Example 50 to obtain thetitle compound having the following physical property values.

Example 50(1)N-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-2-(4-fluorophenyl)acetamide

TLC: Rf 0.47 (hexane:ethyl acetate=2:1);

¹H-NMR (DMSO-d₆): δ 1.70, 3.68, 6.97, 7.12-7.18, 7.35-7.40, 7.67, 10.11.

Example 50(2)N-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-(4-fluorophenyl)propanamide

LC retention time (min), LC condition 1: 0.97;

¹H-NMR (DMSO-d₆): δ 1.70, 2.62-2.67, 2.89-2.94, 6.96, 7.07-7.12,7.27-7.32, 7.66, 9.87.

Example 50(3)N-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-2-[4-(trifluoromethyl)phenyl]acetamide

TLC: Rf 0.70 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 1.71, 3.86, 7.60-7.67.

Example 50(4)N-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3,3-dimethylbutaneamide

TLC: Rf 0.18 (hexane:ethyl acetate=4:1);

¹H-NMR (DMSO-d₆): δ 1.05, 1.70, 2.22, 6.97, 7.67, 9.74.

Example 50(5)N-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[4-(trifluoromethyl)phenyl]propanamide

TLC: Rf 0.50 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.68, 2.70, 3.01, 6.94, 7.48, 7.62-7.65, 9.89.

Example 50(6)N-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[3-(trifluoromethyl)phenyl]propanamide

LC retention time (min), LC condition 2: 1.03;

¹H-NMR (DMSO-d₆): δ 1.69, 2.72, 3.02, 6.94, 7.50-7.65, 9.87.

Example 50(7)N-[2,6-dichloro-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[2-(trifluoromethyl)phenyl]propanamide

LC retention time (min), LC condition 2: 1.03;

¹H-NMR (DMSO-d₆): δ 1.70, 2.67-2.71, 3.06-3.11, 6.95, 7.42, 7.54-7.70,9.94.

Example 51 2-(4-bromo-3-methyl phenyl)-1,1,1-trifluoro-2-propanol

To a tetrahydrofuran solution (40 mL) of 1-(4-bromo-3-methylphenyl)ethanone (4.0 g) (CAS registry number: 37074-40-1),(trifluoromethyl)trimethylsilane (8.3 mL) and tetrabutyl ammoniumfluoride (1 M tetrahydrofuran solution, 0.9 mL) were added underice-cooling. The resulting mixture was stirred at room temperature forone hour. Tetrabutyl ammonium fluoride (1 M tetrahydrofuran solution,22.5 mL) was added to a reaction mixture under ice-cooling, and then thesaturated ammonium chloride aqueous solution was added, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine, dried over sodium sulfate, and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=95:5→85:15) to obtainthe title compound (5.3 g) having the following physical propertyvalues.

TLC: Rf 0.51 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.76, 2.43, 2.48, 7.23-7.26, 7.45, 7.54.

Example 52 2-methyl-2-propanyl[2-methyl-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl] carbamate

To a 1,4-dioxane solution (80 mL) of the compound produced in Example 51(4.5 g), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (1.4 g),palladium acetate (II) (360 mg), tert-butyl carbamate (2.4 g), andcesium carbonate (7.8 g) were added. The resulting mixture was heatedand refluxed for 1.5 hours. The reaction mixture was diluted with ethylacetate. Insoluble matter was separated by filtration through a Celite(product name), and the filtrate was concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=90:10→80:20→60:40) to obtain the titlecompound (1.7 g) having the following physical property values.

TLC: Rf 0.49 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 1.53, 1.75, 2.28, 2.67, 6.32, 7.36-7.39, 7.85-7.89.

Example 53 2-(4-amino-3-methyl phenyl)-1,1,1-trifluoro-2-propanol

To a dichloromethane solution (20 mL) of the compound produced inExample 52 (1.7 g), trifluoroacetic acid (12 mL) was added underice-cooling, and the resulting mixture was stirred at room temperaturefor one hour. Toluene was added to the reaction mixture, followed byconcentration under reduced pressure. A saturated sodiumhydrogencarbonate aqueous solution was added to the resulting residue,followed by extraction with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and then concentrated under reducedpressure to obtain the title compound (743 mg) having the followingphysical property values.

TLC: Rf 0.54 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.73, 2.18, 2.27, 3.66, 6.67, 7.20-7.26.

Example 542-methyl-4-{1,1,1-trifluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

To a tetrahydrofuran solution (15 mL) of the compound produced inExample 53 (743 mg), imidazole (1.15 g) and chlorotrimethylsilane (1.93mL) were added. The resulting mixture was stirred at room temperaturefor one hour. A saturated ammonium chloride aqueous solution was addedto the reaction mixture, followed by extraction with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to obtain the title compound (990 mg) having thefollowing physical property values.

TLC: Rf 0.55 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 0.11, 1.76, 2.17, 3.64, 6.62-6.65, 7.18.

Example 552-chloro-6-methyl-4-{1,1,1-trifluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

To an N,N-dimethylformamide solution (8 mL) of the compound produced inExample 54 (960 mg), N-chlorosuccinimide (439 mg) was added. Theresulting mixture was stirred at room temperature for six hours. Asaturated sodium hydrogencarbonate aqueous solution was added to thereaction mixture, followed by extraction with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=100:0→98:2) to obtain the title compound (619 mg)having the following physical property values.

TLC: Rf 0.47 (hexane:ethyl acetate=8:1);

¹H-NMR (CDCl₃): δ 0.14, 1.75, 2.22, 4.07, 7.11, 7.30.

Example 561-[2-chloro-6-methyl-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea

To a tetrahydrofuran solution (0.4 mL) of solution of the compoundproduced in Example 55 (20 mg), triphosgene (20 mg) and diisopropylethyl amine (11 μL) were added. The resulting mixture was stirred atroom temperature for one hour. The reaction mixture was concentratedunder reduced pressure. The resulting residue was dissolved intetrahydrofuran (0.4 mL), and1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride (19 mg) anddiisopropyl ethyl amine (53 μL) were added thereto. The resultingmixture was stirred at 45° C. for 17 hours. Tetrabutyl ammonium fluoride(1 M tetrahydrofuran solution, 73 μL) was added to the reaction mixture,the resulting mixture was stirred at room temperature for one hour. Asaturated ammonium chloride aqueous solution was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate,and then concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (hexane:ethylacetate=70:30→50:50) to obtain the title compound (20 mg) having thefollowing physical property values.

TLC: Rf 0.47 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 1.78, 2.43, 2.56, 4.80, 5.57, 6.21, 7.43, 7.57, 8.93.

Examples 56(1) to (3)

The corresponding amine instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride was usedand subjected to the same procedure as in Example 56 to obtain the titlecompound having the following physical property values.

Example 56(1)1-[2-chloro-6-methyl-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

TLC: Rf 0.40 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 1.76, 2.38, 2.59, 4.62, 5.55, 6.20, 7.39, 7.47, 7.55,7.91, 8.75.

Example 56(2)1-[2-chloro-6-methyl-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea

TLC: Rf 0.36 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 1.76, 2.37, 2.53, 4.54, 4.89, 5.97, 7.40, 7.56, 7.66,7.86-7.88, 8.64.

Example 56(3)1-[2-chloro-6-methyl-4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-[(5-chloro-2-pyridinyl)methyl]urea

TLC: Rf 0.49 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 1.76, 2.36, 2.50, 4.52, 5.45, 7.30, 7.38, 7.53, 7.65,8.45.

Example 57 2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethanol

To a tetrahydrofuran solution (40 mL) of 3-methyl-4-nitrobenzaldehyde(2.5 g) (CAS registry number: 18515-67-8),(trifluoromethyl)trimethylsilane (6.7 mL) and tetrabutyl ammoniumfluoride (1 M tetrahydrofuran solution, 0.76 mL) were added underice-cooling. The resulting mixture was stirred at room temperature for30 minutes. Tetrabutyl ammonium fluoride (1 M tetrahydrofuran solution,18 mL) was added thereto under ice-cooling, and the resulting mixturewas stirred at room temperature for 30 minutes. A saturated ammoniumchloride aqueous solution was added to the reaction mixture, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel (hexane:ethylacetate=90:10→82:18→50:50) to obtain the title compound (2.0 g) havingthe following physical property values.

TLC: Rf 0.50 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 2.64, 2.89, 5.06-5.14, 7.46-7.49, 7.99-8.02.

Example 58 1-(4-amino-3-methyl phenyl)-2,2,2-trifluoroethanol

To an ethanol solution (90 mL) of the compound produced in Example 57(1.95 g), 5% palladium/carbon (50% water-containing product, 325 mg) wasadded. The resulting mixture was stirred under the hydrogen atmospherefor 1.5 hours. The reaction mixture was diluted with ethyl acetate. Thereaction mixture was filtered through a Celite (product name), and thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by column chromatography on silica gel (hexane:ethylacetate=80:20→67:33→0:100) to obtain the title compound (1.50 g) havingthe following physical property value.

TLC: Rf 0.34 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 2.18, 2.37, 3.72, 4.83-4.92, 6.68, 7.11-7.15.

Example 594-(1-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-2,2,2-trifluoroethyl)-2-methylAniline

To an N,N-dimethylformamide solution (30 mL) of the compound produced inExample 58 (1.50 g), imidazole (2.50 g) and chloro(dimethyl)(2-methyl-2-propanyl)silane (4.94 g) were added. The resulting mixturewas stirred at room temperature for 2.5 hours, and then stirred at 50°C. for one hour. Water was added to the reaction mixture, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=95:5→90:10)to obtain the title compound (507 mg) having the following physicalproperty values.

TLC: Rf 0.63 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 0.11, 0.89, 2.17, 3.66, 4.75-4.81, 6.63-6.66, 7.09.

Example 601-[2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

To a tetrahydrofuran solution (0.6 mL) of the compound produced inExample 59 (30 mg), triphosgene (31 mg) and diisopropyl ethyl amine (17μL) were added. The resulting mixture was stirred at room temperaturefor one hour. The reaction mixture was concentrated under reducedpressure, and the resulting residue was dissolved in tetrahydrofuran(0.6 mL), and 1-[5-(trifluoromethyl)-2-pyridinyl]methanaminehydrochloride (30 mg) and diisopropyl ethyl amine (81 μL) were addedthereto, followed by stirring at room temperature for one hour. To thereaction mixture, tetrabutyl ammonium fluoride (1 M tetrahydrofuransolution, 112 μL) was added. The reaction mixture was stirred at roomtemperature for one hour, and then tetrabutyl ammonium fluoride (1 Mtetrahydrofuran solution, 940 μL) was added. The reaction mixture wasstirred at room temperature for 30 minutes. To the reaction mixture, asaturated ammonium chloride aqueous solution was added, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, concentratedunder reduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=70:30→50:50→30:70) toobtain the title compound (32 mg) having the following physical propertyvalues.

TLC: Rf 0.46 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.22, 4.51, 4.95-5.05, 6.66, 7.18, 7.24, 7.30, 7.58,7.83, 8.02, 8.21, 8.92.

Example 612-chloro-4-(1-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-2,2,2-trifluoroethyl)-6-methylaniline

To an acetonitrile solution (20 mL) of the compound produced in Example59 (470 mg), 1,3-dichloro-5,5-dimethylhydantoin (290 mg) was added. Theresulting mixture was stirred at room temperature for 40 minutes. Asaturated ammonium chloride aqueous solution was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (hexane:ethylacetate=95:5→90:10) to obtain the title compound (435 mg) having thefollowing physical property values.

TLC: Rf 0.58 (hexane:ethyl acetate=8:1);

¹H-NMR (CDCl₃): δ 0.12, 0.91, 2.23, 4.11, 4.73-4.80, 7.04, 7.24.

Example 621-[2-chloro-6-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

The compound produced in Example 61 instead of the compound produced inExample 59 was used and subjected to the same procedure as in Example 60to obtain the title compound having the following physical propertyvalues.

TLC: Rf 0.44 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.23, 4.47, 5.11-5.20, 6.92, 7.03, 7.30, 7.41, 7.57,8.13, 8.23, 8.89.

Examples 62(1) to (3)

The compound produced in Example 61 instead of the compound produced inExample 59, and the corresponding amine instead of1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride were usedand subjected to the same procedure as in Example 60 to obtain the titlecompound having the following physical property values.

Example 62(1)1-[2-chloro-6-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyrimidinyl]methyl}urea

TLC: Rf 0.48 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.22, 4.59, 5.10-5.19, 6.90-6.97, 7.29, 7.40, 8.18,9.24.

Example 62(2)1-[2-chloro-6-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea

TLC: Rf 0.56 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.21, 4.40, 5.11-5.20, 6.92, 6.98, 7.30, 7.41,7.87-7.97, 8.04, 8.67.

Example 62(3)1-[2-chloro-6-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-3-[(5-chloro-2-pyridinyl)methyl]urea

TLC: Rf 0.33 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.22, 4.36, 5.11-5.19, 6.90-6.97, 7.30-7.40, 7.93,8.07, 8.55.

Example 63 2-[4-(dibenzylamino)phenyl]-4,4,4-trifluoro-2-butanol

To a tetrahydrofuran solution (4 mL) of N,N-dibenzyl-4-bromoaniline (300mg) (CAS registry number: 65145-14-4), n-butyllithium (1.64 M hexanesolution, 0.78 mL) was added dropwise at −78° C. The reaction mixturewas stirred at −78° C. for 10 minutes, and then4,4,4-trifluoro-2-butanone (214 mg) was added thereto. The mixture wasstirred at room temperature for one hour. A saturated ammonium chlorideaqueous solution was added to the reaction mixture, followed byextraction with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=85:15) to obtain the title compound(100 mg) having the following physical property values.

TLC: Rf 0.50 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.67, 2.51-2.67, 4.65, 6.68-6.73, 7.22-7.38.

Example 64 2-(4-aminophenyl)-4,4,4-trifluoro-2-butanol

To a mixed solution of methanol (2 mL) and ethyl acetate (2 mL) of thecompound produced in Example 63 (100 mg), 5% palladium/carbon (50% watercontaining product, 10 mg) was added. The reaction mixture was stirredunder the hydrogen atmosphere at room temperature for two hours. Thereaction mixture was filtered through a Celite (product name), and thefiltrate was concentrated under reduced pressure to obtain the titlecompound.

TLC: Rf 0.15 (hexane:ethyl acetate=3:1);

1H-NMR (CD3OD): δ 1.60, 2.56-2.70, 6.83-6.86, 7.31-7.34.

Example 65 4-{4,4,4-trifluoro-2-[(trimethylsilyl)oxy]-2-butanyl}aniline

To a tetrahydrofuran solution (5 mL) of the compound produced in Example64 (54 mg), chlorotrimethylsilane (120 μL) and imidazole (83 mg) wereadded. The resulting mixture was stirred at room temperature for 17hours. A saturated ammonium chloride aqueous solution was added to thereaction mixture, followed by extraction with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=85:15) to obtain thetitle compound (31 mg) having the following physical property values.

TLC: Rf 0.61 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 0.04, 1.74, 2.38-2.60, 3.65, 6.63-6.66, 7.18-7.21.

Example 662,6-dichloro-4-{4,4,4-trifluoro-2-[(trimethylsilyl)oxy]-2-butanyl}aniline

To an N,N-dimethylformamide solution (2 mL) of the compound produced inExample 65 (31 mg), N-chlorosuccinimide (31 mg) was added. The resultingmixture was stirred at 40° C. for 20 hours. Water was added to thereaction mixture, followed by extraction with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=95:5) to obtain thetitle compound (21 mg) having the following physical property values.

TLC: Rf 0.80 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): 0.09, 1.71, 2.37-2.56, 4.42, 7.22.

Example 671-[2,6-dichloro-4-(4,4,4-trifluoro-2-hydroxy-2-butanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

To a dichloromethane solution (2 mL) of the compound produced in Example66 (21 mg), N,N-diisopropyl ethyl amine (11 μL) and triphosgene (19 mg)were added. The resulting mixture was stirred at 40° C. for one hour.The reaction mixture concentrated under reduced pressure, and then, theresulting residue was dissolved in tetrahydrofuran (2 mL).N,N-diisopropyl ethyl amine (50 μL) and1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride (14 mg)were added to the solution, and the solution was stirred at 30° C. for20 hours. A saturated sodium hydrogencarbonate aqueous solution wasadded to the reaction mixture, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was dissolved in tetrahydrofuran (1 mL), andtetrabutyl ammonium fluoride (1 M tetrahydrofuran solution, 582 μL) wasadded, and the solution was stirred at room temperature for one hour. Asaturated ammonium chloride aqueous solution was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (hexane:ethylacetate=50:50) to obtain the title compound (2 mg) having the followingphysical property values.

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 1.69, 2.42, 2.56-2.68, 4.62, 5.81, 6.62, 7.47, 7.49,7.91, 8.76.

Example 68 1-nitro-4-(1,1,1-trifluoro-2-methoxy-2-propanyl)benzene

To an N,N-dimethylformamide solution (13 mL) of the compound produced inExample 1 (1.49 g), sodium hydride (60% in oil, 278 mg) was added underice-cooling. The resulting mixture was stirred at room temperature for15 minutes. Methyl iodide (987 mg) was added to the reaction mixtureunder ice-cooling, the resulting mixture was stirred at room temperaturefor one hour. A saturated ammonium chloride aqueous solution and waterwere added to the reaction mixture under ice-cooling, followed byextraction with ethyl acetate. The organic layer was washed sequentiallywith water and saturated brine, and dried over anhydrous magnesiumsulfate, followed by concentration under reduced pressure. The resultingresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=100:0→80:20) to obtain the title compound (1.55 g)having the following physical property values.

TLC: Rf 0.69 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 1.83, 3.29, 7.70-7.73, 8.25-8.28.

Example 69 4-(1,1,1-trifluoro-2-methoxy-2-propanyl)aniline

To a methanol solution (21 mL) of the compound produced in Example 68(1.55 g), 5% palladium/carbon (50% water-containing product, 155 mg) wasadded. The resulting mixture was stirred under the hydrogen atmosphereat room temperature for two hours. The reaction mixture was filteredthrough a Celite (product name), and then, the filtrate was concentratedto obtain the title compound (1.35 g) having the following physicalproperty values.

TLC: Rf 0.33 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 1.72, 3.19, 3.75, 6.67-6.70, 7.27-7.29.

Example 70 2,6-dichloro-4-(1,1,1-trifluoro-2-methoxy-2-propanyl)aniline

To an acetonitrile solution (25 mL) of the compound produced in Example69 (1.35 g), 1,3-dichloro-5,5-dimethylhydantoin (1.21 g) was added underice-cooling. The resulting mixture was stirred at room temperature forone hour, and then stirred at 45° C. for three hours. An aqueoussolution of sodium sulfite was added to the reaction mixture underice-cooling. The reaction mixture was stirred at room temperature for 30minutes, followed by extraction with ethyl acetate. The organic layerwas washed sequentially with an aqueous solution of sodium sulfite,water, and saturated brine, then dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (hexane:ethylacetate=100:0→80:20) to obtain the title compound (1.74 g) having thefollowing physical property.

TLC: Rf 0.62 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 1.70, 3.22, 4.56, 7.31.

Example 711-[2,6-dichloro-4-(1,1,1-trifluoro-2-methoxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

To a tetrahydrofuran solution (1 mL) of the compound produced in Example70 (30 mg), diisopropyl ethyl amine (20 μL) and triphosgene (34 mg) wereadded. The resulting mixture was stirred at room temperature for 30minutes, followed by concentration under reduced pressure. The resultingresidue was dissolved in tetrahydrofuran (1 mL), and1-[5-(trifluoromethyl)-2-pyridinyl]methanamine hydrochloride (24 mg) andtriethylamine (35 μL) were added thereto. The resulting mixture wasstirred overnight at room temperature. Water was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas washed sequentially with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was washed with hexane-ethyl acetate (9:1) toobtain the title compound (40 mg) having the following physical propertyvalues.

TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.78, 3.19, 4.46, 7.15, 7.54-7.62, 8.23, 8.48, 8.88.

Example 72{[1,1-difluoro-2-(4-nitrophenyl)-2-propanyl]oxy}(trimethyl)silane

To an N,N-dimethylformamide solution (15 mL) of1-(4-nitrophenyl)ethanone (CAS registry number: 100-19-6) (1.00 g),cesium fluoride (183 mg) was added, and (difluoromethyl)(trimethyl)silane (CAS registry number: 65864-64-4) (2.26 g) was addedunder ice-cooling. The reaction mixture was stirred under ice-coolingfor one hour, then stirred at room temperature for two hours, and thenstirred at 45° C. for two hours. Water was added to the reactionmixture, followed extraction with a mixed solvent of ethyl acetate andhexane. The organic layer was washed sequentially with water andsaturated brine, and dried over anhydrous sodium sulfate, followed byconcentration under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel (hexane:ethylacetate=100/0→95/5→65/35→40/60) to obtain the title compound (454 mg)having the following physical property values.

¹H-NMR (CDCl₃): δ 0.17, 1.76, 5.58, 7.66-7.69, 8.21-8.26.

Example 73 4-{1,1-difluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

To a methanol solution (4.1 mL) of the compound produced in Example 72(237 mg), 5% palladium/carbon (manufactured by N.E. CHEMCAT CORPORATION,water-containing product, KER type) (20 mg) was added, and the resultingsolution was stirred under the hydrogen atmosphere at room temperaturefor two hours. The reaction mixture was filtered through a Celite(product name), and the filtrate was concentrated under reduced pressureto obtain the title compound (203 mg) having the following physicalproperty values.

TLC: Rf 0.26 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 0.08, 1.65, 3.68, 5.51, 6.64-6.69, 7.22-7.25.

Example 742,6-dichloro-4-{1,1-difluoro-2-[(trimethylsilyl)oxy]-2-propanyl}aniline

To an N,N-dimethylformamide solution (5.2 mL) of the compound (203 mg)obtained in Example 73, N-chlorosuccinimide (209 mg) was added, and theresulting mixture was stirred at 35° C. for one hour and then stirred at45° C. overnight. The reaction mixture was diluted with a mixed solventof ethyl acetate and hexane, then washed sequentially with water andsaturated brine, and dried over anhydrous sodium sulfate, followed byconcentration under reduced pressure. To a tetrahydrofuran solution (5.2mL) of the resulting residue, imidazole (106 mg) andchlorotrimethylsilane (0.20 mL) were added, and the resulting mixturesolution was stirred at room for two hours. Water was added to thereaction mixture, followed by extraction with ethyl acetate. The organiclayer was washed sequentially with water and saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by column chromatography on silicagel (hexane:ethyl acetate=100/0→95/5→90/10) to obtain the title compound(238 mg) having the following physical property values.

TLC: Rf 0.76 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 0.13, 1.63, 4.47, 5.47, 7.26.

Example 751-[2,6-dichloro-4-(1,1-difluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

The compound produced in Example 74 instead of the compound produced inExample 4 was used and subjected to the same procedure as in Example 5to obtain the title compound having the following physical propertyvalues.

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 1.50, 4.47, 6.02, 7.10, 7.57-7.59, 8.22-8.26, 8.39,8.89.

Example 76 1-(4-amino-3,5-dichlorophenyl)-2,2,2-trifluoroethanone

To an N,N-dimethylformamide solution (30 mL) of1-(4-aminophenyl)-2,2,2-trifluoroethanone (CAS registry number:23516-79-2) (2.60 g), N-chlorosuccinimide (3.70 g) was added, followedby stirring at 40° C. for 18 hours. An aqueous solution of saturatedsodium hydrogencarbonate was added to reaction mixture, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=95/5) toobtain the title compound (3.20 g) having the following physicalproperty values.

TLC: Rf 0.55 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 5.26, 7.94.

Example 77 1-(4-amino-3,5-dichlorophenyl)-2,2,2-trifluoroethanol

To a methanol solution (10 mL) of the compound produced in Example 76(1.00 g), sodium borohydride (146 mg) was added under ice-cooling,followed by stirring at room temperature for one hour. A saturatedammonium chloride aqueous solution was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to obtain the title compound (975mg) having the following physical property values.

¹H-NMR (CDCl₃): δ 4.58, 4.83-4.91, 7.31.

Example 78 4-(1-azide-2,2,2-trifluoroethyl)-2,6-dichloroaniline

To a toluene solution (10 mL) of the compound produced in Example 77(314 mg), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (CAS registrynumber: 41015-70-7) (0.22 mL) and diphenyl phosphorazidate (CAS registrynumber: 26386-88-9) (0.33 mL) were added, followed by stirring at 45° C.for three hours. A saturated sodium hydrogencarbonate aqueous solutionwas added to the reaction mixture, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was purified by column chromatography on silicagel (hexane:ethyl acetate=95/5) to obtain the title compound (314 mg)having the following physical property values.

TLC: Rf 0.70 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 4.65, 4.75, 7.26.

Example 791-[4-(1-amino-2,2,2-trifluoroethyl)-2,6-dichlorophenyl]-3-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea

To a tetrahydrofuran solution (5 mL) of the compound produced in Example78 (310 mg), triphosgene (355 mg) and N,N-diisopropyl ethyl amine (207μL) were added, and the resulting mixture was stirred at roomtemperature for one hour, and then concentrated under reduced pressure.The resulting residue (55 mg) was dissolved in tetrahydrofuran (2 mL),and N,N-diisopropyl ethyl amine (153 μL) and1-[6-(trifluoromethyl)-3-pyridinyl]methanamine (CAS registry number:23586-96-1) (47 mg) were added thereto, followed by stirring at 45° C.for two hours. A saturated sodium hydrogencarbonate aqueous solution wasadded to the reaction mixture, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was dissolved in tetrahydrofuran (2 mL), and water(0.2 mL) and triphenylphosphine (83 mg) were added thereto. Theresulting solution was stirred at room temperature for 30 minutes, andstirred at 50° C. for four hours. The reaction mixture was diluted withwater, followed by extraction with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=20/80) toobtain the title compound (31 mg) having the following physical propertyvalues.

LC retention time (min), LC condition 3:0.72;

¹H-NMR (DMSO-d₆): δ 4.41, 5.34-5.46, 7.18, 7.75, 7.88-7.97, 8.52, 8.68.

Examples 79(1) to (4)

Amine produced in Example 10 or the corresponding amine was used insteadof 1-[6-(trifluoromethyl)-3-pyridinyl]methanamine and subjected to thesame procedure as in Example 79 to obtain a product of the presentinvention having the following physical property values.

Example 79(1)1-[4-(1-amino-2,2,2-trifluoroethyl)-2,6-dichlorophenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

TLC: Rf 0.50 (hexane:ethyl acetate=1:2);

¹H-NMR (CD₃OD): δ 4.61, 5.37-5.45, 7.63-7.66, 7.69, 8.11-8.14, 8.83.

Example 79(2)1-[4-(1-amino-2,2,2-trifluoroethyl)-2,6-dichlorophenyl]-3-[(5-chloro-2-pyridinyl)methyl]urea

LC retention time (min), LC condition 3: 0.66;

¹H-NMR (DMSO-d₆): δ 4.38, 5.42-5.50, 7.14, 7.39, 7.75, 7.94, 8.54-8.56.

Example 79(3)1-[4-(1-amino-2,2,2-trifluoroethyl)-2,6-dichlorophenyl]-3-(4-fluorobenzyl)urea

LC retention time (min), LC condition 3: 0.74;

¹H-NMR (DMSO-d₆): δ 4.26, 5.30-5.40, 6.98, 7.12-7.18, 7.30-7.35, 7.73,8.29.

Example 79(4)1-[4-(1-amino-2,2,2-trifluoroethyl)-2,6-dichlorophenyl]-3-{[2-(trifluoromethyl)-1,3-thiazole-5-yl]methyl}urea

LC retention time (min), LC condition 3: 0.74;

¹H-NMR (DMSO-d₆): δ 4.54, 5.28-5.40, 7.28, 7.74, 7.97, 8.55.

Comparative Example 11-[4-(1,1,1-trifluoro-2-hydroxy-2-propanyl)phenyl]-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

The compound produced in Example 2 instead of the compound produced inExample 4 was used and subjected to the same procedure as in Example 5to obtain the title compound having the following physical propertyvalues.

TLC: Rf 0.25 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 1.63, 4.49, 6.42, 6.86, 7.41, 7.57, 8.18, 8.90.

Comparative Example 2N-(2-bromo-4,6-dichlorophenyl)-2-(4-fluorophenyl)acetamide (Example 1gof Patent Literature 1)

To a toluene solution (8 mL) of 2-bromo-4,6-dichloroaniline (1 g) (CASregistry number: 697-86-9), 4-fluorophenyl acetyl chloride (788 mg) wasadded, followed by stirring at 90° C. overnight. The reaction mixturewas cooled to room temperature, and precipitate was filtered. Theprecipitate was washed with toluene and then dried under reducedpressure at 50° C. to obtain the title compound (1.28 g) having thefollowing physical property values.

TLC: Rf 0.43 (hexane:ethyl acetate=1:1);

¹H-NMR (CD₃OD): δ 3.72, 7.02-7.08, 7.38-7.43, 7.58, 7.69.

The advantageous effects of the compound of the present invention can bedemonstrated by the below-mentioned experiments, but not limitedthereto.

(1) Biological Example 1: Opening Action with Respect to KCNQ2/3 Channelby Depolarization Stimulation

Human KCNQ2/3 expression cells (CHO-DHFR-cells) were seeded in each wellof 384 well plate (collagen-coated, black, clear bottom) at 0.5×10⁴cells/50 μL per well, and cultured in a MEM ALPHA medium (containing 10vol % inactivated (56° C., 30 min) Fetal Bovine Serum and 100 IU/mLPenicillin-100 μg/mL Streptomycin-2 mM L-Glutamine) at 37° C. in 5% CO₂for 18 to 24 hours. The medium in the plate was removed. Then,incubation (room temperature, 60 minutes, light-shielded) was carriedout in a loading buffer (prepared by the method described in the manualof FluxOR Thallium Detection Kit (Invitrogen, F10016, F10017)). KCNQ2/3channel opening action (thallium influx into cells) by thedepolarization stimulation (5 mM potassium and 0.5 mM thallium) wasmeasured by FLIPR TETRA (Molecular Devices). The compound of the presentinvention had been treated five minutes before the depolarizationstimulation, and the reaction induced by the depolarization stimulationwas measured over time for 180 seconds. The channel opening action ofthe compound of the present invention was evaluated based on the changeamount of the fluorescence intensity from the time before thedepolarization stimulation to the time after the passage of 180 seconds.Thus, the concentration (ECrtg50) satisfying 50% of the fluorescenceintensity change of maximum reaction (at the time of 10 μM-treatment) ofretigabine under this experiment condition was calculated.

The KCNQ2/3 channel opening action of the compound of the presentinvention showed 100 μM or less in terms of the ECrtg50 value. Table 1shows the opening action (ECrtg50 values) with respect to the KCNQ2/3channel of the following compounds as representative examples of thecompound of the present invention. As is apparent from Table 1, thecompound of the present invention showed a strong opening action withrespect to the KCNQ2/3 channel. On the other hand, the ECrtg50 value ofthe comparative compound 1 was >10 μM. This shows that it is essentialfor improvement of the KCNQ opening activity of the compound of thepresent invention that at least one of R⁴ and R⁵ in the general formula(I) is a substituent such as halogen.

Furthermore, in the above-mentioned method, when expression cells of thehuman KCNQ4 or human KCNQ5 are used instead of the human KCNQ2/3expression cells and the above-mentioned conditions are appropriatelychanged based on the ordinary knowledge of a person skilled in the art,the opening action with respect to the human KCNQ4 channel or the humanKCNQ5 channel can be measured.

TABLE 1 KCNQ2/3 Compound ECrtg50 (μM) Example 5 (3) 0.5 Example 5 (4)0.003 Example 5 (5) 0.3 Example 5 (6) 0.4 Example 5 (7) 0.5 Example 5(8) 0.001 Example 5 (9) 0.3 Example 5 (10) 0.0003 Example 5 (11) 0.07Example 5 (12) 2.9 Example 5 (13) 0.6 Example 5 (15) 2.3 Example 5 (16)0.01 Example 5 (17) 0.003 Example 5 (19) 0.1 Example 5 (20) 0.5 Example5 (21) 0.07 Example 5 (22) 0.7 Example 13 0.01 Example 22 (1) 0.06Example 22 (2) 0.5 Example 22 (3) 0.2 Example 22 (5) 0.8 Example 22 (15)0.2 Example 22 (16) 0.004 Example 23 0.01 Example 25 (1) 1.4 Example 25(2) 0.3 Example 25 (5) 0.6 Example 25 (6) 0.06 Example 26 0.04 Example32 (1) 0.007 Example 32 (3) 0.5 Example 32 (4) 0.2 Example 33 0.04Example 35 (1) 0.008 Example 35 (3) 0.3 Example 36 0.03 Example 43 (1)0.4 Example 49 0.6 Example 50 (1) 0.06 Example 50 (2) 0.03 Example 50(4) 0.05 Example 50 (6) 0.06 Example 50 (7) 0.04 Example 60 1.7 Example62 0.06 Example 67 3.5 Example 71 0.2 Example 75 0.4 Example 79 (1) 1.6Example 79 (4) 0.3 Comparative >10 Example 1 Comparative 0.2 Example 2

(2) Biological Example 2: Relaxing Action on Urinary Bladder Extractedfrom Rat

Female Jcl Wistar rats (CLEA Japan, Inc., body weight in use: 170 to 200g) were anesthetized by intraperitoneal administration of about 40 mg/kgof pentobarbital (Somnopentyl, Schering Plough Animal HealthCorporation), and killed by bloodletting, followed by abdominal incisionto extract the urinary bladder. Immediately, the extracted urinarybladder was immersed in ice-cooled Krebs buffer (Krebs Ringerbicarbonate buffer (Sigma-Aldlich Co.) containing sodiumhydrogencarbonate (final concentration: 15 mM) and calcium chloride(final concentration: 2.5 mM)) which had been saturated with a mixed gas(95% O₂, 5% CO₂).

The urinary bladder bodies were cut in the longitudinal direction toprepare strip specimens (about 10×3 mm) on ice. Immediately, theprepared specimens were suspended in a Magnus tube with 500 mg oftension loaded. The tube was filled with Krebs buffer (37° C.) aeratedwith a mixed gas. Note here that specimens were prepared within 24 hoursafter extraction of the tissue.

Change of tension of the specimens was recorded in data collectionsystem (NR-1000, KEYENCE CORPORATION) using a Magnus system equippedwith isometric transducer (UFER UM-203, Iwashiya Kishimoto MedicalInstruments) and an amplifier (UFER AP-5, Iwashiya Kishimoto MedicalInstruments), and displayed on the computer via recorder analysissoftware WAVE THERMO 1000 (KEYENCE CORPORATION). When one hour or morehad passed after the specimen was suspended, 2.5M KCl was added so thatthe final concentration became 100 mM, specimens showing contractionreaction were used.

Carbachol (a contraction-inducing substance) at the concentration ofcontraction of 1 μM was used to induce contraction. The substances werearbitrarily assigned in groups so that difference in the degree ofcontraction was not generated between groups and the specimens harvestedfrom the same individual did not belong to the same group. After thecontraction reaction was stabilized, a physiological salt solution orthe compound of the present invention was added in a cumulative mannerfrom low concentration such that the final concentration became 1, 10,100 nM, 1 and 10 μM.

The tension (mg) of the extracted urinary bladder was employed as anevaluation parameter. The tension was read by using analysis softwareWAVE THERMO 1000. Tension after addition of the contraction-inducingsubstance was set to 0%. The change rate of the tension after additionof the compound of the present invention relative to the tension afteraddition of the contraction-inducing substance was defined as tensionchange rate (%). The tension change rate (%) was adopted as anevaluation indicator. The tension change rate (%) is calculated from thefollowing formula.

Tension change rate (%)={Tension after addition of compound of thepresent invention and the like (mg)−Tension before addition ofcontraction-inducing substance (mg)}/{Tension after addition ofcontraction-inducing substance (mg)−Tension before addition ofcontraction-inducing substance (mg)}×100−100

The value at which the tension change rate (%) was −20% was calculatedas IC₂₀, and the value was adopted as an indicator of the relaxingaction of the extracted urinary bladder.

Table 2 shows IC₂₀ values in the rat Magnus test of the followingcompounds as representative examples of the compound of the presentinvention. As is apparent from Table 2, the compound of the presentinvention had relaxing action with respect to the extracted rat urinarybladder. Consequently, the compound of the present invention is usefulas a therapeutic agent for overactive urinary bladder.

TABLE 2 Rat Magnus test Compound IC₂₀ (uM) Example 22 (1) 0.3 Example 22(2) 0.4 Example 22 (3) 0.3 Example 22 (5) 0.3 Example 23 0.1 Example 25(1) 0.6 Example 25 (2) 0.2 Example 25 (5) 0.5 Example 26 0.2 Example 32(1) 0.02 Example 32 (3) 0.1 Example 32 (4) 0.2 Example 33 0.03 Example35 (1) 0.02 Example 35 (3) 0.1 Example 36 0.01

(3) Solubility Test

A calibration curve solution was prepared by diluting a test substance(10 mM DMSO solution) with acetonitrile and adding acetonitrileincluding an internal standard substance (candesartan) so as to be 0.1,0.4, and 2 μM.

Sample solution was prepared as follows: 5 μL of the compound of thepresent invention (10 mM DMSO solution) was added to 495 μL of thePharmacopoeia of Japan elution test second solution (pH=6.8), and theresulting mixture was stirred at room temperature for five hours. Then,the solution was placed into a solubility filter plate and subjected tosuction filtration. The filtrate (20 μL) was diluted with acetonitrile,followed by adding acetonitrile including an internal standard substance(CANDESARTAN).

The calibration curve and sample solutions in the amount of 5 μL wereinfused into LC-MS/MS (Discovery Max manufactured by Thermo Scientific)and subjected to quantitation (quantitation range: 5 to 100 μM). Thesolubility was set to <5 μM when the value was less than thequantitation range, and the solubility was set to 100 μM when the valuewas more than the quantitation range.

The results are shown in Table 3. As is apparent from Table 3, thecompounds shown in Table 3 as the representative examples of thecompound of the present invention showed excellent solubility. On thecontrary, the solubility of Comparative Example 2 (Example 1g of PatentLiterature 1) was not more than the detection limit (<5 μM), showingthat the solubility of Comparative Example 2 was low.

TABLE 3 Compound Solubility (uM) Example 5 (4) 79 Example 5 (5) 93Example 5 (6) 94 Example 5 (9) 91 Example 5 (13) 81 Example 5 (15) 90Example 5 (19) 76 Example 5 (20) 100 Example 5 (22) 85 Example 13 69Example 22 (1) 77 Example 22 (2) 89 Example 22 (3) 81 Example 22 (5) 91Example 23 46 Example 25 (1) 96 Example 25 (2) 86 Example 25 (5) 98Example 25 (6) 40 Example 26 59 Example 32 (1) 100 Example 32 (3) 100Example 32 (4) 77 Example 33 91 Example 35 (1) 100 Example 35 (3) 87Example 36 44 Example 43 (1) 89 Example 50 (1) 82 Example 50 (2) 41Example 62 71 Example 79 (1) 87 Comparative <5 Example 2

(4) Evaluation of Stability in Human Liver Microsome

A test compound (10 mmol/L DMSO solution, 5 μL) was diluted with 50%acetonitrile aqueous solution (195 μL) to prepare 0.25 mmol/L solution.

To a reactor vessel which had been warmed to 37° C. in advance, 0.5mg/mL of human liver microsome (Xenotech) and 245 μL of 0.1 M phosphatebuffer solution (pH 7.4) including NADPH-Co-factor (BD Biosciences) wereadded, followed by preincubation for five minutes. Then, theabove-mentioned test compound solution (5 μL) was added so as to startreaction (final concentration: 5 μmol/L). Immediately after the start,20 μL was harvested and added to 180 μL of acetonitrile including aninternal standard substance (warfarin) to stop the reaction. Thissolution (20 μL) was stirred with 180 μL of 50% acetonitrile aqueoussolution on a plate equipped with a deproteinization filter. Then, theresulting mixture solution was subjected to suction filtration. Thefiltrate was adopted as a standard sample.

The above-mentioned reaction solution was incubated at 37° C. for 15minutes, and 20 μL of the solution was added to 180 μL of cooledacetonitrile (including warfarin that is an internal standard substance)to stop the reaction. This solution (20 μL) was stirred with 180 μL of50% acetonitrile aqueous solution on a plate equipped with adeproteinization filter, and then the resulting mixture solution wassubjected to suction filtration. The filtrate was adopted as a reactionsample.

Residual rate (%) was obtained as follows: 1 μL of the sample solutionwas infused into LC-MS/MS (Discovery Max manufactured by ThermoScientific), and a quotient obtained by dividing a peak area ratio ofthe reaction sample (peak area of test compound/peak area of internalstandard substance) was divided by the peak area ratio of the standardsample was multiplied by 100.

The results are shown in Table 4. As is apparent from Table 4, thecompounds shown in Table 4 shown as the representative examples of thecompound of the present invention showed high stability with respect toa human liver microsome, showing that the compound is excellent in themetabolic stability.

TABLE 4 Residual Compound rate (%) Example 5 (13) 75 Example 5 (15) 97Example 5 (19) 100 Example 5 (20) 91 Example 22 (1) 100 Example 22 (2)100 Example 22 (3) 98 Example 22 (5) 99 Example 22 (15) 93 Example 22(16) 94 Example 23 100 Example 25 (1) 78 Example 25 (2) 80 Example 25(5) 87 Example 25 (6) 73 Example 26 64 Example 32 (3) 100 Example 32 (4)100 Example 33 100 Example 35 (1) 100 Example 35 (3) 100 Example 36 100Example 50 (1) 96 Example 50 (4) 100 Example 60 98 Example 75 100Example 79 (1) 82

(5) Evaluation of Action on hERG IKr Current

Using HEK293 cell overexpressing a human ether-a-go-go-related gene(hERG), the maximum tale current of the hERG IKr current induced byredepolarization pulse subsequent to depolarization pulse was measuredby a patch-clamp method. The change rate (inhibition rate) of the 10minutes after application of the test compound, with respect to themaximum tale current before application of the test compound, wascalculated (see, Biophysical Journal, Vol. 74, 230-241 (1998)). Theresults are shown in Table 5. As is apparent from Table 5, the compoundsshown in Table 5 as the representative examples of the compounds of thepresent invention showed that the 50% inhibitory activity of hERGchannel thereof were >10 μM and less possibility of inducing Q-Textension due to drug, showing that the compounds the present inventionhad excellent safety.

TABLE 5 Compound IC₅₀ (uM) Example 22 (1) >10 Example 22 (2) >10 Example22 (3) >10 Example 22 (5) >10 Example 23 >10 Example 25 (1) >10 Example25 (2) >10 Example 25 (5) >10 Example 26 >10 Example 32 (3) >10 Example32 (4) >10 Example 33 >10 Example 35 (3) >10 Example 36 >10 Example 50(1) >10 Example 79 (1) >10

Formulation Example

Representative formulation examples to be used in the present inventionare shown as follows.

Formulation Example 1

The following components were mixed with each other in a usual methodand punched out to obtain 10,000 tablets each containing 10 mg of theactive ingredient.

1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea(100 g);

carboxymethylcellulose calcium (disintegrating agent) (20 g);

magnesium stearate (lubricant) (10 g);

microcrystalline cellulose (870 g).

Formulation Example 2

The following components were mixed with each other in a usual methodand filtered with a dust removal filter, and 5 mL each of the filtratewas filled into ampoules. The ampoules were heated and sterilized in anautoclave, thereby obtaining 10,000 ampoules each containing 20 mg ofthe active ingredient.

1-{2,6-dichloro-4-[(2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}-3-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea(200 g);

mannitol (2 kg);

distilled water (50 L).

INDUSTRIAL APPLICABILITY

The compound of the present invention has sufficiently low toxicity, andcan be used safely as a pharmaceutical agent, and useful as atherapeutic agent for KCNQ2-5 channel-related diseases.

1-11. (canceled) 12.1-[(5-chloro-2-pyridinyl)methyl]-3-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea,or a pharmaceutically acceptable salt thereof. 13.-19. (canceled) 20.1-[(5-chloro-2-pyridinyl)methyl]-3-{2,6-dichloro-4-[(2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl]phenyl}urea.